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1. The Role of Eomes in the Maintenance of CD8+ Tissue-Resident Memory T cells

Author: Duong, Han G
Subjects: Biology, Immunology, CD8, Eomes, T cells, tissue resident
Abstract: CD8+ tissue-resident memory T cells play a well-established role in host defense againstmicrobial pathogens but have also been recently implicated in playing a role in the pathogenesisof inflammatory and autoimmune diseases. Previous work demonstrated that the T-boxtranscription factor Eomes is extinguished during the formation of skin TRM cells owing to TGF-ꞵ signaling. However, our lab previously observed high expression of Eomes in a pathogenicCD8+ TRM subset enriched in patients with ulcerative colitis, a form of inflammatory boweldisease. Thus, we sought to investigate the role of Eomes in the maintenance of TRM in smallintestine and colon tissue compartments. We adoptively transferred congenically distinct wildtypeand Eomesfl/fl ER-Cre+ CD8+ P14 cells into recipient mice and infected them with LCMV.We administered tamoxifen injections to inducibly delete Eomes at 30 days post-infection afterthe formation of TRM cells. Our results suggest that Eomes plays a previously unappreciatedfunction in intestinal TRM maintenance through a potential role in regulating tissue damage andTGF-ꞵ responsiveness.
Published: 2021

2. The broader phenotypic spectrum of congenital caudal abnormalities associated with mutations in the caudal type homeobox 2 gene

Author: Marjon van Slegtenhorst, Paul Lasko, Jill R. Murrell, Romy van de Putte, Courtney Manning, Mary-Alice Abbott, Constance T. R. M. Stumpel, Jacqueline Leonard, Iris A.L.M. van Rooij, Servi J. C. Stevens, Han G. Brunner, Alexander Hoischen, Karin E. M. Diderich, Louise C. Pyle, Jorune Balciuniene, MUMC+: DA KG Lab Centraal Lab (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Polikliniek (9), Klinische Genetica, MUMC+: DA Klinische Genetica (5), and Clinical Genetics
Subjects: Male, Pathology, medicine.medical_specialty, caudal regression syndrome, Genotype, SACRAL AGENESIS, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Biology, Sacral Agenesis, persistent cloaca, sirenomelia, Vertebral segmentation defect, homeobox gene, Exome Sequencing, VACTERL, Genetics, medicine, Humans, Abnormalities, Multiple, CDX2 Transcription Factor, Genetic Predisposition to Disease, imperforate anus, Genetic Testing, Child, CDX2, Alleles, Genetic Association Studies, Genetics (clinical), Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Caudal regression syndrome, ELONGATION, Sacrococcygeal Region, Infant, Newborn, Infant, medicine.disease, HOX, Phenotype, digestive system diseases, Reconstructive and regenerative medicine Radboud Institute for Health Sciences [Radboudumc 10], Sirenomelia, Mutation, embryonic structures, Homeobox, GROWTH, Female, PARAHOX, Imperforate anus
Abstract: Contains fulltext : 248942.pdf (Publisher’s version ) (Open Access) The caudal type homeobox 2 (CDX2) gene encodes a developmental regulator involved in caudal body patterning. Only three pathogenic variants in human CDX2 have been described, in patients with persistent cloaca, sirenomelia and/or renal and anogenital malformations. We identified five patients with de novo or inherited pathogenic variants in CDX2 with clinical phenotypes that partially overlap with previous cases, that is, imperforate anus and renal, urogenital and limb abnormalities. However, additional clinical features were seen including vertebral agenesis and we describe considerable phenotypic variability, even in unrelated patients with the same recurrent p.(Arg237His) variant. We propose CDX2 variants as rare genetic cause for a multiple congenital anomaly syndrome that can include features of caudal regression syndrome and VACTERL. A causative role is further substantiated by the relationship between CDX2 and other proteins encoded by genes that were previously linked to caudal abnormalities in humans, for example, TBXT (sacral agenesis and other vertebral segmentation defects) and CDX1 (anorectal malformations). Our findings confirm the essential role of CDX2 in caudal morphogenesis and formation of cloacal derivatives in humans, which to date has only been well characterized in animals.
Published: 2022

3. The landscape of autosomal-recessive pathogenic variants in European populations reveals phenotype-specific effects

Author: Han G. Brunner, Ephrat Levy-Lahad, Chris Tyler-Smith, Massimo Mezzavila, Christian Gilissen, Reedik Mägi, Andres Metspalu, Yali Xue, Reidar Andreson, Shai Carmi, Hila Fridman, Helger G. Yntema, RS: GROW - R4 - Reproductive and Perinatal Medicine, Klinische Genetica, and MUMC+: DA Klinische Genetica (5)
Subjects: Male, at-risk couples, autosomal recessive disorders, carrier frequency, pre-conception carrier screening, selection, Cohort Studies, Europe, Exome, Female, Genes, Recessive, Genetic Testing, Genetic Variation, Health, Heterozygote, Humans, Intellectual Disability, Whites, Consanguinity, Family Characteristics, Phenotype, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Genetics (clinical), Genetics, 0303 health sciences, education.field_of_study, 030305 genetics & heredity, Genetic disorder, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], GENOME, GENES, GENETICS, Population, Biology, Article, White People, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, medicine, Recessive, Allele, education, Gene, 030304 developmental biology, Carrier signal, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], MUTATIONS, medicine.disease, Genetic architecture
Abstract: The number and distribution of recessive alleles in the population for various diseases are not known at genome-wide-scale. Based on 6447 exome-sequences of healthy, genetically-unrelated Europeans of two distinct ancestries, we estimate that every individual is a carrier of at least 2 pathogenic variants in currently known autosomal recessive (AR) genes, and that 0.8-1% of European couples are at-risk of having a child affected with a severe AR genetic disorder. This risk is 16.5-fold higher for first cousins, but is significantly more increased for skeletal disorders and intellectual disabilities due to their distinct genetic architecture.
Published: 2021

4. Truncating SRCAP variants outside the Floating-Harbor syndrome locus cause a distinct neurodevelopmental disorder with a specific DNA methylation signature

Author: Ian R. Berry, Martin R. Larsen, Ann M. Neumeyer, Lilian Bomme Ousager, Leah J. Rowe, Richard E. Person, Chanika Phornphutkul, David A. Koolen, Constance T. R. M. Stumpel, Konrad Platzer, Elizabeth J. Bhoj, Eric Chater-Diehl, Jason Bunn, Erika Leenders, Koen L.I. van Gassen, Joshua Charkow, Rosanna Weksberg, Ny Hoang, Roos Cuperus, Davor Lessel, Rolph Pfundt, Oana Caluseriu, Sarah J. Goodman, Leandra Folk, Fanggeng Zou, Michelle T. Siu, David Chitayat, Dmitrijs Rots, Jeroen R. Vermeulen, Shuxi Liu, Cheryl Cytrynbaum, Elin Tønne, Hein Brackel, Mareike Mertens, Jennifer Campbell, Jonathan B. Strober, Maja Hempel, Tjitske Kleefstra, Małgorzata J.M. Nowaczyk, Amy Crunk, Marta Pacio-Míguez, Fernando Santos-Simarro, Nicola Brunetti-Pierri, Christa de Geus, María Palomares-Bralo, Lisenka E.L.M. Vissers, Sander Pajusalu, Peter Kannu, Sanaa Choufani, Kristin Lindstrom, Margarita Saenz, Berkley Schmidt, Daniëlle G.M. Bosch, Han G. Brunner, Arie van Haeringen, Ellen van Binsbergen, Brianna Pruniski, Claudia A. L. Ruivenkamp, William G. Wilson, Servi J. C. Stevens, Susan Walker, Kristian Tveten, Zain Awamleh, Gerarda Cappuccio, Alexander J. M. Dingemans, Michael Kwint, Ebba Alkhunaizi, Jonas Denecke, Alyssa Ritter, Eric W. Klee, Bert B.A. de Vries, Jeske V.T. van Harssel, Stephen Meyn, A. Chantal Deden, Francisca Millan, Eva Morava, Ingrid M. Wentzensen, Anne Slavotinek, Stephen W. Scherer, Katrin Õunap, Tuula Rinne, Jessica A. Radley, Yili Xie, Thatjana Gardeitchik, Laura Schultz-Rogers, Karit Reinson, Ronald D. Cohn, Hui Yang, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Polikliniek (9), Klinische Genetica, MUMC+: DA KG Lab Centraal Lab (9), Klinische Neurowetenschappen, MUMC+: MA Med Staf Spec Neurologie (9), RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, MUMC+: DA Klinische Genetica (5), Rots, Dmitrij, Chater-Diehl, Eric, Dingemans, Alexander J M, Goodman, Sarah J, Siu, Michelle T, Cytrynbaum, Cheryl, Choufani, Sanaa, Hoang, Ny, Walker, Susan, Awamleh, Zain, Charkow, Joshua, Meyn, Stephen, Pfundt, Rolph, Rinne, Tuula, Gardeitchik, Thatjana, de Vries, Bert B A, Deden, A Chantal, Leenders, Erika, Kwint, Michael, Stumpel, Constance T R M, Stevens, Servi J C, Vermeulen, Jeroen R, van Harssel, Jeske V T, Bosch, Danielle G M, van Gassen, Koen L I, van Binsbergen, Ellen, de Geus, Christa M, Brackel, Hein, Hempel, Maja, Lessel, Davor, Denecke, Jona, Slavotinek, Anne, Strober, Jonathan, Crunk, Amy, Folk, Leandra, Wentzensen, Ingrid M, Yang, Hui, Zou, Fanggeng, Millan, Francisca, Person, Richard, Xie, Yili, Liu, Shuxi, Ousager, Lilian B, Larsen, Martin, Schultz-Rogers, Laura, Morava, Eva, Klee, Eric W, Berry, Ian R, Campbell, Jennifer, Lindstrom, Kristin, Pruniski, Brianna, Neumeyer, Ann M, Radley, Jessica A, Phornphutkul, Chanika, Schmidt, Berkley, Wilson, William G, Õunap, Katrin, Reinson, Karit, Pajusalu, Sander, van Haeringen, Arie, Ruivenkamp, Claudia, Cuperus, Roo, Santos-Simarro, Fernando, Palomares-Bralo, María, Pacio-Míguez, Marta, Ritter, Alyssa, Bhoj, Elizabeth, Tønne, Elin, Tveten, Kristian, Cappuccio, Gerarda, Brunetti-Pierri, Nicola, Rowe, Leah, Bunn, Jason, Saenz, Margarita, Platzer, Konrad, Mertens, Mareike, Caluseriu, Oana, Nowaczyk, Małgorzata J M, Cohn, Ronald D, Kannu, Peter, Alkhunaizi, Ebba, Chitayat, David, Scherer, Stephen W, Brunner, Han G, Vissers, Lisenka E L M, Kleefstra, Tjitske, Koolen, David A, and Weksberg, Rosanna
Subjects: 0301 basic medicine, Heart Septal Defects, Ventricular, Male, DNA methylation signature, nonsense-mediated decay, speech delay, PROTEIN, 030105 genetics & heredity, PHENOTYPE, epigenomic, Medical and Health Sciences, Epigenesis, Genetic, Craniofacial Abnormalities, Cohort Studies, Neurodevelopmental disorder, 2.1 Biological and endogenous factors, Aetiology, Genetics (clinical), Growth Disorders, Epigenomics, non-FLHS SRCAP-related NDD, Genetics, Adenosine Triphosphatases, Genetics & Heredity, neurodevelopmental disorders, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], SOTOS-LIKE, Biological Sciences, SRCAP, Hypotonia, AT-HOOK, 3. Good health, Phenotype, Mental Health, intellectual disability, Speech delay, DNA methylation, Female, medicine.symptom, Abnormalities, Multiple, EXON 34, Intellectual and Developmental Disabilities (IDD), Locus (genetics), Biology, genotype-phenotype correlation, DIAGNOSIS, Article, 03 medical and health sciences, Genetic, Clinical Research, medicine, Humans, Abnormalities, Multiple, Genetic Predisposition to Disease, Floating-Harbor syndrome, SPECTRUM, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], MUTATIONS, Heart Septal Defects, Infant, Newborn, Ventricular, dNaM, Infant, DNA Methylation, medicine.disease, Newborn, neurodevelopmental disorder, GENE, Brain Disorders, 030104 developmental biology, Floating–Harbor syndrome, Case-Control Studies, Mutation, epigenomics, EPISIGNATURES, Epigenesis
Abstract: Contains fulltext : 234078.pdf (Publisher’s version ) (Open Access) Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein (SRCAP) gene cause the neurodevelopmental disorder (NDD) Floating-Harbor syndrome (FLHS), characterized by short stature, speech delay, and facial dysmorphism. Here, we present a cohort of 33 individuals with clinical features distinct from FLHS and truncating (mostly de novo) SRCAP variants either proximal (n = 28) or distal (n = 5) to the FLHS locus. Detailed clinical characterization of the proximal SRCAP individuals identified shared characteristics: developmental delay with or without intellectual disability, behavioral and psychiatric problems, non-specific facial features, musculoskeletal issues, and hypotonia. Because FLHS is known to be associated with a unique set of DNA methylation (DNAm) changes in blood, a DNAm signature, we investigated whether there was a distinct signature associated with our affected individuals. A machine-learning model, based on the FLHS DNAm signature, negatively classified all our tested subjects. Comparing proximal variants with typically developing controls, we identified a DNAm signature distinct from the FLHS signature. Based on the DNAm and clinical data, we refer to the condition as "non-FLHS SRCAP-related NDD." All five distal variants classified negatively using the FLHS DNAm model while two classified positively using the proximal model. This suggests divergent pathogenicity of these variants, though clinically the distal group presented with NDD, similar to the proximal SRCAP group. In summary, for SRCAP, there is a clear relationship between variant location, DNAm profile, and clinical phenotype. These results highlight the power of combined epigenetic, molecular, and clinical studies to identify and characterize genotype-epigenotype-phenotype correlations.
Published: 2021

5. Long-read trio sequencing of individuals with unsolved intellectual disability

Author: Erdi Kucuk, Shreyasee Chakraborty, Marcel R. Nelen, Han G. Brunner, Lisenka E.L.M. Vissers, Primo Baybayan, Michael Kwint, Bart van der Sanden, Alexander Hoischen, Ronny Derks, Marc Pauper, Aaron M. Wenger, Christian Gilissen, MUMC+: DA Klinische Genetica (5), Klinische Genetica, and RS: GROW - R4 - Reproductive and Perinatal Medicine
Subjects: Proband, Concordance, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], DE-NOVO, Biology, VARIANTS, Genome, Article, 03 medical and health sciences, symbols.namesake, 0302 clinical medicine, Genetics, Coding region, HUMAN GENOME, DNA sequencing, Gene, Genetics (clinical), Exome sequencing, 030304 developmental biology, UTILITY, 0303 health sciences, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Other Research Radboud Institute for Health Sciences [Radboudumc 0], Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], DISCOVERY, Mendelian inheritance, symbols, Structural variation, 030217 neurology & neurosurgery, Reference genome
Abstract: Contains fulltext : 235027.pdf (Publisher’s version ) (Open Access) Long-read sequencing (LRS) has the potential to comprehensively identify all medically relevant genome variation, including variation commonly missed by short-read sequencing (SRS) approaches. To determine this potential, we performed LRS around 15×-40× genome coverage using the Pacific Biosciences Sequel I System for five trios. The respective probands were diagnosed with intellectual disability (ID) whose etiology remained unresolved after SRS exomes and genomes. Systematic assessment of LRS coverage showed that ~35 Mb of the human reference genome was only accessible by LRS and not SRS. Genome-wide structural variant (SV) calling yielded on average 28,292 SV calls per individual, totaling 12.9 Mb of sequence. Trio-based analyses which allowed to study segregation, showed concordance for up to 95% of these SV calls across the genome, and 80% of the LRS SV calls were not identified by SRS. De novo mutation analysis did not identify any de novo SVs, confirming that these are rare events. Because of high sequence coverage, we were also able to call single nucleotide substitutions. On average, we identified 3 million substitutions per genome, with a Mendelian inheritance concordance of up to 97%. Of these, ~100,000 were located in the ~35 Mb of the genome that was only captured by LRS. Moreover, these variants affected the coding sequence of 64 genes, including 32 known Mendelian disease genes. Our data show the potential added value of LRS compared to SRS for identifying medically relevant genome variation.
Published: 2020

6. Contribution of Intellectual Disability–Related Genes to ADHD Risk and to Locomotor Activity in Drosophila

Author: Lambertus A. Kiemeney, Nina Roth Mota, Anne van Rens, Monique van der Voet, Alejandro Arias-Vásquez, Euginia L. Singgih, Han G. Brunner, Anna Castells-Nobau, Ditte Demontis, Marieke Klein, Barbara Franke, Annette Schenck, and Anders D. Børglum
Subjects: behavioral disciplines and activities, Locomotor activity, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, 0302 clinical medicine, Intellectual Disability, mental disorders, Intellectual disability, Genetics, medicine, ADHD, Attention deficit hyperactivity disorder, Drosophila (subgenus), MEF2C, Gene, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], biology, business.industry, biology.organism_classification, medicine.disease, 030227 psychiatry, Psychiatry and Mental health, Drosophila melanogaster, Neuropsychiatric disorder, TRAPPC9, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], business, Neuroscience, 030217 neurology & neurosurgery
Abstract: OBJECTIVE: Attention deficit hyperactivity disorder (ADHD) is a common, highly heritable neuropsychiatric disorder. ADHD often co-occurs with intellectual disability, and shared overlapping genetics have been suggested. The aim of this study was to identify novel ADHD genes by investigating whether genes carrying rare mutations linked to intellectual disability contribute to ADHD risk through common genetic variants. Validation and characterization of candidates were performed using Drosophila melanogaster. METHODS: Common genetic variants in a diagnostic gene panel of 396 autosomal intellectual disability genes were tested for association with ADHD risk through gene set and gene-wide analyses, using ADHD meta-analytic data from the Psychiatric Genomics Consortium for discovery (N=19,210) and ADHD data from the Lundbeck Foundation Initiative for Integrative Psychiatric Research for replication (N=37,076). The significant genes were functionally validated and characterized in Drosophila by assessing locomotor activity and sleep upon knockdown of those genes in brain circuits. RESULTS: The intellectual disability gene set was significantly associated with ADHD risk in the discovery and replication data sets. The three genes most consistently associated were MEF2C, ST3GAL3, and TRAPPC9. Performing functional characterization of the two evolutionarily conserved genes in Drosophila melanogaster, the authors found that their knockdown in dopaminergic (dMEF2) and circadian neurons (dTRAPPC9) resulted in increased locomotor activity and reduced sleep, concordant with the human phenotype. CONCLUSIONS: This study reveals that a large set of intellectual disability-related genes contribute to ADHD risk through effects of common alleles. Utilizing this continuity, the authors identified TRAPPC9, MEF2C, and ST3GAL3 as novel ADHD candidate genes. Characterization in Drosophila suggests that TRAPPC9 and MEF2C contribute to ADHD-related behavior through distinct neural substrates.
Published: 2020

7. Mutations in RPSA and NKX2-3 link development of the spleen and intestinal vasculature

Author: Anthony P. Williams, Martin W. Laass, Paul Fockens, Alexander P.A. Stegmann, Chantal Kerkhofs, Han G. Brunner, William Rae, Rune Østern, Freddy Kokke, Servi J. C. Stevens, Saul N. Faust, Christiane Würfel, Peter Wurm, MUMC+: DA KG Polikliniek (9), MUMC+: DA KG Lab Centraal Lab (9), Kindergeneeskunde, MUMC+: MA Medische Staf Kindergeneeskunde (9), MUMC+: DA Klinische Genetica (5), Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, Gastroenterology and Hepatology, AGEM - Digestive immunity, and AGEM - Re-generation and cancer of the digestive system
Subjects: Male, Candidate gene, Pathology, Organogenesis, homeobox gene, whole-exome sequencing, Intestinal varices, Genetics (clinical), Exome sequencing, Research Articles, IDIOPATHIC COLONIC VARICES, Sanger sequencing, 0303 health sciences, 030305 genetics & heredity, Pedigree, Intestines, medicine.anatomical_structure, symbols, Female, whole‐exome sequencing, medicine.symptom, NKX2-3, NKX2‐3, Research Article, Ribosomal Proteins, Asplenia, medicine.medical_specialty, Nonsense mutation, asplenia, Spleen, Biology, FAMILIAL VARICES, Receptors, Laminin, 03 medical and health sciences, symbols.namesake, intestinal varices, All institutes and research themes of the Radboud University Medical Center, Exome Sequencing, Genetics, medicine, Humans, Genetic Predisposition to Disease, Genetic Association Studies, 030304 developmental biology, CONGENITAL ASPLENIA, Homeodomain Proteins, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Genetic Variation, TRANSCRIPTION FACTOR NKX2-3, Sequence Analysis, DNA, medicine.disease, RPSA, MICE, Mutation, Blood Vessels, Transcription Factors
Abstract: Idiopathic intestinal varicosis is a developmental disorder defined by dilated and convoluted submucosal veins in the colon or small bowel. A limited number of families with idiopathic intestinal varices has been reported, but the genetic cause has not yet been identified. We performed whole exome and targeted Sanger sequencing of candidate genes in five intestinal varicosis families. In four families mutations in the RPSA gene were found, a gene previously linked to congenital asplenia. Individuals in these pedigrees had intestinal varicose veins and angiodysplasias, often in combination with asplenia. In a further four generation pedigree that only showed intestinal varicosities, the RPSA gene was normal. Instead, a nonsense mutation in the homeobox gene NKX2-3 was detected which co-segregated with the disease in this large family with a LOD score of 3.3. NKX2-3 is a component of a molecular pathway underlying spleen and gut vasculature development in mice. Our results provide a molecular basis for familial idiopathic intestinal varices. We provide evidence for a relationship between the molecular pathways underlying the development of the spleen and intestinal mucosal vasculature that is conserved between humans and mice. We propose that clinical management of intestinal varices, should include assessment of a functional spleen. This article is protected by copyright. All rights reserved.
Published: 2020

8. Cellular Self-Digestion and Persistence in Bacteria

Author: Prashant Karki, Shayne Sensenbach, Vahideh Angardi, Mehmet A. Orman, Han G Ngo, Sayed Golam Mohiuddin, Narendra K. Dewangan, and Sreyashi Ghosh
Subjects: Microbiology (medical), Proteases, autophagy, QH301-705.5, Review, Protein degradation, Microbiology, Persistence (computer science), stationary-phase metabolism, RNA degradation, Virology, Extracellular, Biology (General), intracellular degradation, chemistry.chemical_classification, biology, Autophagy, biology.organism_classification, viable but non-culturable cells, Cell biology, self-digestion, bacterial persisters, Enzyme, chemistry, protein degradation, lipid degradation, Bacteria, Intracellular
Abstract: Cellular self-digestion is an evolutionarily conserved process occurring in prokaryotic cells that enables survival under stressful conditions by recycling essential energy molecules. Self-digestion, which is triggered by extracellular stress conditions, such as nutrient depletion and overpopulation, induces degradation of intracellular components. This self-inflicted damage renders the bacterium less fit to produce building blocks and resume growth upon exposure to fresh nutrients. However, self-digestion may also provide temporary protection from antibiotics until the self-digestion-mediated damage is repaired. In fact, many persistence mechanisms identified to date may be directly or indirectly related to self-digestion, as these processes are also mediated by many degradative enzymes, including proteases and ribonucleases (RNases). In this review article, we will discuss the potential roles of self-digestion in bacterial persistence.
Published: 2021

9. De Novo Variants Disturbing the Transactivation Capacity of POU3F3 Cause a Characteristic Neurodevelopmental Disorder

Author: Christopher Cunniff, Laurence Faivre, Simon E. Fisher, Hester Y. Kroes, Catherine Au, Rolph Pfundt, Jacqueline Leonard, Ahmad N. Abou Tayoun, Kosuke Izumi, Katherine Bergstrom, Deepali N. Shinde, Pelagia Deriziotis, Saskia M. Maas, Marcello Niceta, Antonio Vitobello, Sha Tang, Hanka Venselaar, Christophe Philippe, Christian Gilissen, Tjitske Kleefstra, Marco Tartaglia, Helen V. Firth, Nobuhiko Okamoto, Laurens Wiel, Lot Snijders Blok, Naomichi Matsumoto, Maria Lisa Dentici, Han G. Brunner, Samuel W. Baker, Susan Tomkins, Augusta M. A. Lachmeijer, Simon Bodek, Alejandro D. Iglesias, Monica H. Wojcik, Katrin Õunap, Noriko Miyake, Koen L.I. van Gassen, Zöe Powis, The DDD Study, Human Genetics, ANS - Complex Trait Genetics, MUMC+: DA Klinische Genetica (5), Klinische Genetica, and RS: GROW - R4 - Reproductive and Perinatal Medicine
Subjects: 0301 basic medicine, Male, Protein Conformation, Sequence Homology, Language in Interaction, Transactivation, 0302 clinical medicine, Neurodevelopmental disorder, BINDING, Transcriptional regulation, Missense mutation, Genetics(clinical), speech/language disorder, BRET assay, Child, de novo variants, luciferase reporter, Genetics (clinical), Genetics, TRANSCRIPTIONAL REGULATION, POU3F3, FOXP2, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], POU3F2, SPEECH, Brain-1, intellectual disability, Female, Neuroinformatics, Transcriptional Activation, EXPRESSION, GENES, Genotype, PROTEINS, Biology, BRN-2, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Report, medicine, Humans, Amino Acid Sequence, Allele, Gene, Transcription factor, Genetic Association Studies, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], medicine.disease, 030104 developmental biology, Gene Expression Regulation, Neurodevelopmental Disorders, Mutation, POU Domain Factors, HOMODIMERIZATION, Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19], 030217 neurology & neurosurgery
Abstract: POU3F3, also referred to as Brain-1, is a well-known transcription factor involved in the development of the central nervous system, but it has not previously been associated with a neurodevelopmental disorder. Here, we report the identification of 19 individuals with heterozygous POU3F3 disruptions, most of which are de novo variants. All individuals had developmental delays and/or intellectual disability and impairments in speech and language skills. Thirteen individuals had characteristic low-set, prominent, and/or cupped ears. Brain abnormalities were observed in seven of eleven MRI reports. POU3F3 is an intronless gene, insensitive to nonsense-mediated decay, and 13 individuals carried protein-truncating variants. All truncating variants that we tested in cellular models led to aberrant subcellular localization of the encoded protein. Luciferase assays demonstrated negative effects of these alleles on transcriptional activation of a reporter with a FOXP2-derived binding motif. In addition to the loss-of-function variants, five individuals had missense variants that clustered at specific positions within the functional domains, and one small in-frame deletion was identified. Two missense variants showed reduced transactivation capacity in our assays, whereas one variant displayed gain-of-function effects, suggesting a distinct pathophysiological mechanism. In bioluminescence resonance energy transfer (BRET) interaction assays, all the truncated POU3F3 versions that we tested had significantly impaired dimerization capacities, whereas all missense variants showed unaffected dimerization with wild-type POU3F3. Taken together, our identification and functional cell-based analyses of pathogenic variants in POU3F3, coupled with a clinical characterization, implicate disruptions of this gene in a characteristic neurodevelopmental disorder.
Published: 2019

10. De Novo and Inherited Pathogenic Variants in KDM3B Cause Intellectual Disability, Short Stature, and Facial Dysmorphism

Author: Laurence Perrin, Marjolijn C.J. Jongmans, Isabelle Thiffault, Han G. Brunner, Bethany Peri, Sarah K. Bartz, Alexandra Afenjar, Kristina Baltrunaite, Esmé Waanders, Jayne Y. Hehir-Kwa, Illja J. Diets, Boris Keren, Alexander J. M. Dingemans, Gea Beunders, Roland P. Kuiper, Anneke T. Vulto-van Silfhout, Laurens Wiel, Bert Callewaert, Andrew Dauber, Margot R.F. Reijnders, Tjitske Kleefstra, Vivian Hwa, Caroline Nava, Matias Wagner, Matthias Griese, Lina Huerta-Saenz, Roos van der Donk, Rolph Pfundt, Nicoline Hoogerbrugge, Christian Gilissen, Maxime Cadieux-Dion, Julia Vodopiutz, Koen L.I. van Gassen, Annekatrien Boel, Julien Thevenon, Nienke E. Verbeek, Bert B.A. de Vries, Vassiliki Konstantopoulou, Human genetics, MUMC+: DA KG Polikliniek (9), MUMC+: DA Klinische Genetica (5), Klinische Genetica, and RS: GROW - R4 - Reproductive and Perinatal Medicine
Subjects: 0301 basic medicine, Male, Jumonji Domain-Containing Histone Demethylases, Developmental Disabilities, WEAVER SYNDROME, PROTEIN, Haploinsufficiency, Craniofacial Abnormalities, Histones, 0302 clinical medicine, Intellectual disability, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Missense mutation, DEMETHYLASE KDM3B, Exome, Child, Genetics (clinical), Exome sequencing, Genetics, RUBINSTEIN-TAYBI SYNDROME, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Phenotype, 030220 oncology & carcinogenesis, Female, medicine.symptom, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Joint hypermobility, GENETICS, JMJD1C, Mutation, Missense, Dwarfism, Biology, Short stature, Kdm3b, Cancer Predisposition, Developmental Delay, Facial Recognition, Intellectual Disability, Leukemia, Lymphoma, Short Stature, 03 medical and health sciences, Report, medicine, Humans, MYELOID-LEUKEMIA, Genetic Association Studies, Germ-Line Mutation, Weaver syndrome, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Rubinstein–Taybi syndrome, MUTATIONS, DELETION, Genetic Variation, medicine.disease, Body Height, Musculoskeletal Abnormalities, INDIVIDUALS, 030104 developmental biology, Face, Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19]
Abstract: Contains fulltext : 202646.pdf (Publisher’s version ) (Open Access) By using exome sequencing and a gene matching approach, we identified de novo and inherited pathogenic variants in KDM3B in 14 unrelated individuals and three affected parents with varying degrees of intellectual disability (ID) or developmental delay (DD) and short stature. The individuals share additional phenotypic features that include feeding difficulties in infancy, joint hypermobility, and characteristic facial features such as a wide mouth, a pointed chin, long ears, and a low columella. Notably, two individuals developed cancer, acute myeloid leukemia and Hodgkin lymphoma, in childhood. KDM3B encodes for a histone demethylase and is involved in H3K9 demethylation, a crucial part of chromatin modification required for transcriptional regulation. We identified missense and truncating variants, suggesting that KDM3B haploinsufficiency is the underlying mechanism for this syndrome. By using a hybrid facial-recognition model, we show that individuals with a pathogenic variant in KDM3B have a facial gestalt, and that they show significant facial similarity compared to control individuals with ID. In conclusion, pathogenic variants in KDM3B cause a syndrome characterized by ID, short stature, and facial dysmorphism.
Published: 2019

11. Author Correction: CHD3 helicase domain mutations cause a neurodevelopmental syndrome with macrocephaly and impaired speech and language

Author: Snijders Blok, Lot, Rousseau, Justine, Twist, Joanna, Ehresmann, Sophie, Takaku, Motoki, Venselaar, Hanka, Rodan, Lance H., Nowak, Catherine B., Douglas, Jessica, Swoboda, Kathryn J., Steeves, Marcie A., Sahai, Inderneel, Stumpel, Connie T. R. M., Stegmann, Alexander P. A., Wheeler, Patricia, Willing, Marcia, Fiala, Elise, Kochhar, Aaina, Gibson, William T., Cohen, Ana S. A., Agbahovbe, Ruky, Innes, A. Micheil, Au, P. Y. Billie, Rankin, Julia, Anderson, Ilse J., Skinner, Steven A., Louie, Raymond J., Warren, Hannah E., Afenjar, Alexandra, Keren, Boris, Nava, Caroline, Buratti, Julien, Isapof, Arnaud, Rodriguez, Diana, Lewandowski, Raymond, Propst, Jennifer, van Essen, Ton, Choi, Murim, Lee, Sangmoon, Chae, Jong H., Price, Susan, Schnur, Rhonda E., Douglas, Ganka, Wentzensen, Ingrid M., Zweier, Christiane, Reis, André, Bialer, Martin G., Moore, Christine, Koopmans, Marije, Brilstra, Eva H., Monroe, Glen R., van Gassen, Koen L. I., van Binsbergen, Ellen, Newbury-Ecob, Ruth, Bownass, Lucy, Bader, Ingrid, Mayr, Johannes A., Wortmann, Saskia B., Jakielski, Kathy J., Strand, Edythe A., Kloth, Katja, Bierhals, Tatjana, McRae, Jeremy F., Clayton, Stephen, Fitzgerald, Tomas W., Kaplanis, Joanna, Prigmore, Elena, Rajan, Diana, Sifrim, Alejandro, Aitken, Stuart, Akawi, Nadia, Alvi, Mohsan, Ambridge, Kirsty, Barrett, Daniel M., Bayzetinova, Tanya, Jones, Philip, Jones, Wendy D., King, Daniel, Krishnappa, Netravathi, Mason, Laura E., Singh, Tarjinder, Tivey, Adrian R., Ahmed, Munaza, Anjum, Uruj, Archer, Hayley, Armstrong, Ruth, Awada, Jana, Balasubramanian, Meena, Banka, Siddharth, Baralle, Diana, Barnicoat, Angela, Batstone, Paul, Baty, David, Bennett, Chris, Berg, Jonathan, Bernhard, Birgitta, Bevan, A. Paul, Bitner-Glindzicz, Maria, Blair, Edward, Blyth, Moira, Bohanna, David, Bourdon, Louise, Bourn, David, Bradley, Lisa, Brady, Angela, Brent, Simon, Brewer, Carole, Brunstrom, Kate, Bunyan, David J., Burn, John, Canham, Natalie, Castle, Bruce, Chandler, Kate, Chatzimichali, Elena, Cilliers, Deirdre, Clarke, Angus, Clasper, Susan, Clayton-Smith, Jill, Clowes, Virginia, Coates, Andrea, Cole, Trevor, Colgiu, Irina, Collins, Amanda, Collinson, Morag N., Connell, Fiona, Cooper, Nicola, Cox, Helen, Cresswell, Lara, Cross, Gareth, Crow, Yanick, D’Alessandro, Mariella, Dabir, Tabib, Davidson, Rosemarie, Davies, Sally, de Vries, Dylan, Dean, John, Deshpande, Charu, Devlin, Gemma, Dixit, Abhijit, Dobbie, Angus, Donaldson, Alan, Donnai, Dian, Donnelly, Deirdre, Donnelly, Carina, Douglas, Angela, Douzgou, Sofia, Duncan, Alexis, Eason, Jacqueline, Ellard, Sian, Ellis, Ian, Elmslie, Frances, Evans, Karenza, Everest, Sarah, Fendick, Tina, Fisher, Richard, Flinter, Frances, Foulds, Nicola, Fry, Andrew, Fryer, Alan, Gardiner, Carol, Gaunt, Lorraine, Ghali, Neeti, Gibbons, Richard, Gill, Harinder, Goodship, Judith, Goudie, David, Gray, Emma, Green, Andrew, Greene, Philip, Greenhalgh, Lynn, Gribble, Susan, Harrison, Rachel, Harrison, Lucy, Harrison, Victoria, Hawkins, Rose, He, Liu, Hellens, Stephen, Henderson, Alex, Hewitt, Sarah, Hildyard, Lucy, Hobson, Emma, Holden, Simon, Holder, Muriel, Holder, Susan, Hollingsworth, Georgina, Homfray, Tessa, Humphreys, Mervyn, Hurst, Jane, Hutton, Ben, Ingram, Stuart, Irving, Melita, Islam, Lily, Jackson, Andrew, Jarvis, Joanna, Jenkins, Lucy, Johnson, Diana, Jones, Elizabeth, Josifova, Dragana, Joss, Shelagh, Kaemba, Beckie, Kazembe, Sandra, Kelsell, Rosemary, Kerr, Bronwyn, Kingston, Helen, Kini, Usha, Kinning, Esther, Kirby, Gail, Kirk, Claire, Kivuva, Emma, Kraus, Alison, Kumar, Dhavendra, Kumar, V. K. Ajith, Lachlan, Katherine, Lam, Wayne, Lampe, Anne, Langman, Caroline, Lees, Melissa, Lim, Derek, Longman, Cheryl, Lowther, Gordon, Lynch, Sally A., Magee, Alex, Maher, Eddy, Male, Alison, Mansour, Sahar, Marks, Karen, Martin, Katherine, Maye, Una, McCann, Emma, McConnell, Vivienne, McEntagart, Meriel, McGowan, Ruth, McKay, Kirsten, McKee, Shane, McMullan, Dominic J., McNerlan, Susan, McWilliam, Catherine, Mehta, Sarju, Metcalfe, Kay, Middleton, Anna, Miedzybrodzka, Zosia, Miles, Emma, Mohammed, Shehla, Montgomery, Tara, Moore, David, Morgan, Sian, Morton, Jenny, Mugalaasi, Hood, Murday, Victoria, Murphy, Helen, Naik, Swati, Nemeth, Andrea, Nevitt, Louise, Norman, Andrew, O’Shea, Rosie, Ogilvie, Caroline, Ong, Kai-Ren, Park, Soo-Mi, Parker, Michael J., Patel, Chirag, Paterson, Joan, Payne, Stewart, Perrett, Daniel, Phipps, Julie, Pilz, Daniela T., Pollard, Martin, Pottinger, Caroline, Poulton, Joanna, Pratt, Norman, Prescott, Katrina, Pridham, Abigail, Procter, Annie, Purnell, Hellen, Quarrell, Oliver, Ragge, Nicola, Rahbari, Raheleh, Randall, Josh, Raymond, Lucy, Rice, Debbie, Robert, Leema, Roberts, Eileen, Roberts, Jonathan, Roberts, Paul, Roberts, Gillian, Ross, Alison, Rosser, Elisabeth, Saggar, Anand, Samant, Shalaka, Sampson, Julian, Sandford, Richard, Sarkar, Ajoy, Schweiger, Susann, Scott, Richard, Scurr, Ingrid, Selby, Ann, Seller, Anneke, Sequeira, Cheryl, Shannon, Nora, Sharif, Saba, Shaw-Smith, Charles, Shearing, Emma, Shears, Debbie, Sheridan, Eamonn, Simonic, Ingrid, Singzon, Roldan, Skitt, Zara, Smith, Audrey, Smith, Kath, Smithson, Sarah, Sneddon, Linda, Splitt, Miranda, Squires, Miranda, Stewart, Fiona, Stewart, Helen, Straub, Volker, Suri, Mohnish, Sutton, Vivienne, Swaminathan, Ganesh Jawahar, Sweeney, Elizabeth, Tatton-Brown, Kate, Taylor, Cat, Taylor, Rohan, Tein, Mark, Temple, I. Karen, Thomson, Jenny, Tischkowitz, Marc, Tomkins, Susan, Torokwa, Audrey, Treacy, Becky, Turner, Claire, Turnpenny, Peter, Tysoe, Carolyn, Vandersteen, Anthony, Varghese, Vinod, Vasudevan, Pradeep, Vijayarangakannan, Parthiban, Vogt, Julie, Wakeling, Emma, Wallwark, Sarah, Waters, Jonathon, Weber, Astrid, Wellesley, Diana, Whiteford, Margo, Widaa, Sara, Wilcox, Sarah, Wilkinson, Emily, Williams, Denise, Williams, Nicola, Wilson, Louise, Woods, Geoff, Wragg, Christopher, Wright, Michael, Yates, Laura, Yau, Michael, Nellåker, Chris, Parker, Michael, Firth, Helen V., Wright, Caroline F., FitzPatrick, David R., Barrett, Jeffrey C., Hurles, Matthew E., Roberts, John D., Petrovich, Robert M., Machida, Shinichi, Kurumizaka, Hitoshi, Lelieveld, Stefan, Pfundt, Rolph, Jansen, Sandra, Deriziotis, Pelagia, Faivre, Laurence, Thevenon, Julien, Assoum, Mirna, Shriberg, Lawrence, Kleefstra, Tjitske, Brunner, Han G., Wade, Paul A., Fisher, Simon E., and Campeau, Philippe M.
Subjects: Male, Models, Molecular, Developmental Disabilities, Gene Expression, General Physics and Astronomy, 02 engineering and technology, Chromatin remodelling, Sociology, lcsh:Science, Independent research, Adenosine Triphosphatases, 0303 health sciences, Multidisciplinary, biology, Health innovation, Disease genetics, Published Erratum, Neurodevelopmental disorders, 021001 nanoscience & nanotechnology, Spelling, 3. Good health, Phenotype, General partnership, Child, Preschool, ComputingMethodologies_DOCUMENTANDTEXTPROCESSING, Female, medicine.symptom, Construct (philosophy), 0210 nano-technology, Psychology, Mi-2 Nucleosome Remodeling and Deacetylase Complex, Clinical epigenetics, Genotype, Science, Mutation, Missense, Library science, Child health, Speech Disorders, General Biochemistry, Genetics and Molecular Biology, Domain (software engineering), 03 medical and health sciences, Protein Domains, Intellectual Disability, medicine, Humans, Author Correction, 030304 developmental biology, Research ethics, Language Disorders, Whole Genome Sequencing, Core Grant, Macrocephaly, DNA Helicases, Helicase, General Chemistry, Chromatin Assembly and Disassembly, Megalencephaly, HEK293 Cells, biology.protein, lcsh:Q, Neuroscience, Impaired speech
Abstract: An Author Correction to this article was published on 15 February 2019 An Author Correction to this article was published on 02 May 2019 We thank all individuals and families for their contribution. We thank Amaia Carrion Castillo and Else Eising for assistance with the WGS analysis of the index individual, and Sarah Graham and Elliot Sollis for cloning the wild-type CHD3 construct for immunofluorescence. This work was supported by the Netherlands Organization for Scientific Research (NWO) Gravitation Grant 24.001.006 to the Language in Interaction Consortium (L.S.B., S.E.F., and H.G.B.), the Max Planck Society (S.E.F.), the National Institute on Deafness and Other Communication Disorders Grant DC000496 (L.Sh.) and a core grant to the Waisman Center from the National Institute of Child Health and Human Development (Grant U54 HD090256) to L.Sh., the Canadian Institutes of Health Research Grants MOP-119595 and PJT-148830 to W.T.G. Individuals 11, 16, 24, and 28 were part of The DDD Study cohort. The DDD Study presents independent research commissioned by the Health Innovation Challenge Fund [Grant number HICF-1009-003], a parallel funding partnership between the Wellcome Trust and the Department of Health, and the Wellcome Trust Sanger Institute [Grant number WT098051]. The views expressed in this publication are those of the author(s) and not necessarily those of the Wellcome Trust or the Department of Health. The DDD study has UK Research Ethics Committee approval (10/H0305/83, granted by the Cambridge South REC, and GEN/284/12, granted by the Republic of Ireland REC). The research team acknowledges the support of the National Institute for Health Research, through the Comprehensive Clinical Research Network.
Published: 2019

12. Expansion of mutation-driven haematopoietic clones is associated with insulin resistance and low HDL-cholesterol in individuals with obesity

Author: Christian Gilissen, Marc Pieterse, Felipe M. Kristensson, Markku Peltonen, Björn Carlsson, Lena M. S. Carlsson, Peter Jacobson, Johanna C. Andersson-Assarsson, Rosanne C. van Deuren, Alexander Hoischen, Han G. Brunner, Mihai G. Netea, Marloes Steehouwer, Kajsa Sjöholm, Per-Arne Svensson, Magdalena Taube, and Rosie Perkins
Subjects: Genetics, Mutation, Somatic cell, Clone (cell biology), Biology, Molecular Inversion Probe, medicine.disease, medicine.disease_cause, Blood cell, Haematopoiesis, medicine.anatomical_structure, Insulin resistance, medicine, Gene
Abstract: AimsHaematopoietic clones caused by somatic mutations with ≥2% variant allele frequency (VAF), known as clonal haematopoiesis of indeterminate potential (CHIP), increase with age and have been linked to risk of haematological malignancies and cardiovascular disease. Recent observations suggest that smaller clones are also associated with adverse clinical outcomes. Our aims were to determine the prevalence of clonal haematopoiesis driven by clones of variable sizes, and to examine the development of clones over time in relation to age and metabolic dysregulation over up to 20 years in individuals with obesity.Methods and ResultsWe used an ultrasensitive single-molecule molecular inversion probe sequencing assay to identify clonal haematopoiesis driver mutations (CHDMs) in blood samples from individuals with obesity from the Swedish Obese Subjects study. In a single-timepoint dataset with samples from 1050 individuals, we identified 273 candidate CHDMs in 216 individuals, with VAF ranging from 0.01% to 31.15% and CHDM prevalence and clone sizes increasing with age. Longitudinal analysis over 20 years in CHDM-positive samples from 40 individuals showed that small clones can grow over time and become CHIP. VAF increased on average by 7% (range -4% to 27%) per year. Rate of clone growth was positively associated with insulin resistance (R=0.40, P=0.025) and low circulating levels of high-density lipoprotein-cholesterol (HDL-C) (R=-0.68, P=1.74E-05).ConclusionOur results show that haematopoietic clones can be detected and monitored before they become CHIP and indicate that insulin resistance and low HDL-C, well-established cardiovascular risk factors, are associated with clonal expansion in individuals with obesity.Translational perspectivesClonal haematopoiesis-driver mutations are somatic mutations in haematopoietic stem cells that lead to clones detectable in peripheral blood. Haematopoietic clones with a variant allele frequency (VAF) ≥2%, known as clonal haematopoiesis of indeterminate potential (CHIP), are recognized as an independent cardiovascular risk factor. Here, we show that smaller clones are prevalent, and also correlate with age. Our longitudinal observations in individuals with obesity over 20 years showed that more than half of all clone-positive individuals show growing clones and clones with VAF Translational outlook 1: Haematopoietic clones can be detected and monitored before they become CHIP.Translational outlook 2: The association between insulin resistance and low HDL-C with growth of haematopoietic clones opens the possibility that treatments improving metabolism, such as weight loss, may reduce growth of clones and thereby cardiovascular risk.One Sentence SummaryIn obesity, the growth rate of mutation-driven haematopoietic clones increased with insulin resistance and low HDL-C, both known risk factors for cardiovascular disease.
Published: 2021

13. Monoamine oxidase A activity in fibroblasts as a functional confirmation of MAOA variants

Author: Nicole de Leeuw, Michèl A.A.P. Willemsen, Marcel M. Verbeek, Karlien L.M. Coene, Ron A. Wevers, Tessa M. A. Peters, Irma Lammerts van Bueren, Jon J. Jonsson, Han G. Brunner, Ben P.B.H. Geurtz, MUMC+: DA Klinische Genetica (5), Klinische Genetica, and RS: GROW - R4 - Reproductive and Perinatal Medicine
Subjects: Research Report, enzyme assay, lcsh:QH426-470, Endocrinology, Diabetes and Metabolism, Aldehyde dehydrogenase, MAO‐A deficiency, medicine.disease_cause, lcsh:Diseases of the endocrine glands. Clinical endocrinology, Biochemistry, Genetics and Molecular Biology (miscellaneous), High-performance liquid chromatography, Internal Medicine, medicine, Fibroblast, Gene, functional confirmation, Mutation, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], lcsh:RC648-665, biology, Chemistry, variant of uncertain significance, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Research Reports, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], medicine.disease, Molecular biology, Enzyme assay, lcsh:Genetics, medicine.anatomical_structure, Inborn error of metabolism, biology.protein, HPLC, Monoamine oxidase A
Abstract: Monoamine oxidase A (MAO‐A) deficiency is a rare inborn error of metabolism with impaired degradation of biogenic amines including 5‐hydroxytryptamine (5‐HT), resulting in borderline intellectual disability and behavioral abnormalities. Genetic variants in MAOA need functional confirmation to enable a definite diagnosis. To this end, we developed an inexpensive, simple and nonradioactive MAO‐A activity assay based on the conversion of 5‐HT into 5‐hydroxyindoleacetic acid (5‐HIAA). Fibroblast cell lysates were incubated with 5‐HT and aldehyde dehydrogenase to allow 5‐HIAA production. 5‐HIAA was quantified using high‐performance liquid chromatography with fluorimetric detection. We optimized reaction mixture components, pH, and substrate concentration and tested linearity and specificity of the assay. We verified the functional validity of the enzyme assay using fibroblasts of controls, female mutation carriers and MAO‐A deficient patients. This included a newly described patient with a novel MAOA variant (c.1336G>A, p.(Glu446Lys)), who represents the fifth MAO‐A deficiency family so far. The optimized enzyme assay showed good linearity and specificity. Application to clinical samples showed a 100% differentiation of affected patients (with negligible MAO‐A enzyme activity) and controls or mutation carriers. In conclusion, the described MAO‐A activity assay is easy to implement and can readily be used to test the pathogenicity of variants in the MAOA gene in a clinical setting. Especially in this era of whole‐exome (and whole‐genome) sequencing, this functional assay fulfills a clinical need for functional confirmation of a suspected diagnosis of MAO‐A deficiency.
Published: 2021

14. Solve-RD: systematic pan-European data sharing and collaborative analysis to solve rare diseases

Author: Zurek, Birte, Ellwanger, Kornelia, Vissers, Lisenka E. L. M., Schüle, Rebecca, Synofzik, Matthis, Töpf, Ana, de Voer, Richarda M., Laurie, Steven, Matalonga, Leslie, Gilissen, Christian, Ossowski, Stephan, ’t Hoen, Peter A. C., Vitobello, Antonio, Schulze-Hentrich, Julia M., Riess, Olaf, Brunner, Han G., Brookes, Anthony J., Rath, Ana, Bonne, Gisèle, Gumus, Gulcin, Verloes, Alain, Hoogerbrugge, Nicoline, Evangelista, Teresinha, Harmuth, Tina, Swertz, Morris, Spalding, Dylan, Hoischen, Alexander, Beltran, Sergi, Graessner, Holm, Haack, Tobias B., Demidov, German, Sturm, Marc, Kessler, Christoph, Wayand, Melanie, Wilke, Carlo, Traschütz, Andreas, Schöls, Ludger, Hengel, Holger, Heutink, Peter, Brunner, Han, Scheffer, Hans, Steyaert, Wouter, Sablauskas, Karolis, Kamsteeg, Erik-Jan, van de Warrenburg, Bart, van Os, Nienke, te Paske, Iris, Janssen, Erik, de Boer, Elke, Steehouwer, Marloes, Yaldiz, Burcu, Kleefstra, Tjitske, Veal, Colin, Gibson, Spencer, Wadsley, Marc, Mehtarizadeh, Mehdi, Riaz, Umar, Warren, Greg, Dizjikan, Farid Yavari, Shorter, Thomas, Straub, Volker, Bettolo, Chiara Marini, Specht, Sabine, Clayton-Smith, Jill, Banka, Siddharth, Alexander, Elizabeth, Jackson, Adam, Faivre, Laurence, Thauvin, Christel, Denommé-Pichon, Anne-Sophie, Duffourd, Yannis, Tisserant, Emilie, Bruel, Ange-Line, Peyron, Christine, Pélissier, Aurore, Gut, Ivo Glynne, Piscia, Davide, Papakonstantinou, Anastasios, Bullich, Gemma, Corvo, Alberto, Garcia, Carles, Fernandez-Callejo, Marcos, Hernández, Carles, Picó, Daniel, Paramonov, Ida, Lochmüller, Hanns, Bros-Facer, Virginie, Hanauer, Marc, Olry, Annie, Lagorce, David, Havrylenko, Svitlana, Izem, Katia, Rigour, Fanny, Stevanin, Giovanni, Durr, Alexandra, Davoine, Claire-Sophie, Guillot-Noel, Léna, Heinzmann, Anna, Coarelli, Giulia, Allamand, Valérie, Nelson, Isabelle, Yaou, Rabah Ben, Metay, Corinne, Eymard, Bruno, Cohen, Enzo, Atalaia, Antonio, Stojkovic, Tanya, Macek, Milan, Turnovec, Marek, Thomasová, Dana, Kremliková, Radka Pourová, Franková, Vera, Havlovicová, Markéta, Kremlik, Vlastimil, Parkinson, Helen, Keane, Thomas, Senf, Alexander, Robinson, Peter, Danis, Daniel, Robert, Glenn, Costa, Alessia, Patch, Christine, Hanna, Mike, Houlden, Henry, Reilly, Mary, Vandrovcova, Jana, Muntoni, Francesco, Zaharieva, Irina, Sarkozy, Anna, Timmerman, Vincent, Baets, Jonathan, Van de Vondel, Liedewei, Beijer, Danique, de Jonghe, Peter, Nigro, Vincenzo, Banfi, Sandro, Torella, Annalaura, Musacchia, Francesco, Piluso, Giulio, Ferlini, Alessandra, Selvatici, Rita, Rossi, Rachele, Neri, Marcella, Aretz, Stefan, Spier, Isabel, Sommer, Anna Katharina, Peters, Sophia, Oliveira, Carla, Pelaez, Jose Garcia, Matos, Ana Rita, José, Celina São, Ferreira, Marta, Gullo, Irene, Fernandes, Susana, Garrido, Luzia, Ferreira, Pedro, Carneiro, Fátima, Swertz, Morris A., Johansson, Lennart, van der Velde, Joeri K., van der Vries, Gerben, Neerincx, Pieter B., Roelofs-Prins, Dieuwke, Köhler, Sebastian, Metcalfe, Alison, Drunat, Séverine, Rooryck, Caroline, Trimouille, Aurelien, Castello, Raffaele, Morleo, Manuela, Pinelli, Michele, Varavallo, Alessandra, De la Paz, Manuel Posada, Sánchez, Eva Bermejo, Martín, Estrella López, Delgado, Beatriz Martínez, de la Rosa, F. Javier Alonso García, Ciolfi, Andrea, Dallapiccola, Bruno, Pizzi, Simone, Radio, Francesca Clementina, Tartaglia, Marco, Renieri, Alessandra, Benetti, Elisa, Balicza, Peter, Molnar, Maria Judit, Maver, Ales, Peterlin, Borut, Münchau, Alexander, Lohmann, Katja, Herzog, Rebecca, Pauly, Martje, Macaya, Alfons, Marcé-Grau, Anna, Osorio, Andres Nascimiento, de Benito, Daniel Natera, Thompson, Rachel, Polavarapu, Kiran, Beeson, David, Cossins, Judith, Cruz, Pedro M. Rodriguez, Hackman, Peter, Johari, Mridul, Savarese, Marco, Udd, Bjarne, Horvath, Rita, Capella, Gabriel, Valle, Laura, Holinski-Feder, Elke, Laner, Andreas, Steinke-Lange, Verena, Schröck, Evelin, Rump, Andreas, Groningen Institute for Gastro Intestinal Genetics and Immunology (3GI), RS: GROW - R4 - Reproductive and Perinatal Medicine, Klinische Genetica, MUMC+: DA Klinische Genetica (5), Zurek, Birte [0000-0002-8200-7542], Ellwanger, Kornelia [0000-0003-4845-5795], Vissers, Lisenka ELM [0000-0001-6470-5497], Synofzik, Matthis [0000-0002-2280-7273], de Voer, Richarda M [0000-0002-8222-0343], Laurie, Steven [0000-0003-3913-5829], Gilissen, Christian [0000-0003-1693-9699], 't Hoen, Peter AC [0000-0003-4450-3112], Vitobello, Antonio [0000-0003-3717-8374], Brookes, Anthony J [0000-0001-8686-0017], Rath, Ana [0000-0003-4308-6337], Bonne, Gisèle [0000-0002-2516-3258], Verloes, Alain [0000-0003-4819-0264], Hoogerbrugge, Nicoline [0000-0003-2393-8141], Harmuth, Tina [0000-0002-4833-8057], Spalding, Dylan [0000-0002-4285-2493], Beltran, Sergi [0000-0002-2810-3445], Graessner, Holm [0000-0001-9803-7183], Apollo - University of Cambridge Repository, Zurek, B., Ellwanger, K., Vissers, L. E. L. M., Schule, R., Synofzik, M., Topf, A., de Voer, R. M., Laurie, S., Matalonga, L., Gilissen, C., Ossowski, S., 't Hoen, P. A. C., Vitobello, A., Schulze-Hentrich, J. M., Riess, O., Brunner, H. G., Brookes, A. J., Rath, A., Bonne, G., Gumus, G., Verloes, A., Hoogerbrugge, N., Evangelista, T., Harmuth, T., Swertz, M., Spalding, D., Hoischen, A., Beltran, S., Graessner, H., Nigro, V., Banfi, S., Torella, A., Piluso, G., Dürr, Alexandra, Lohmann, Katja, Kessler, Christoph, Wayand, Melanie, Wilke, Carlo, Traschuetz, Andreas, Schöls, Ludger, Hengel, Holger, Heutink, Peter, University of Tübingen, Radboud University Medical Center [Nijmegen], Newcastle Upon Tyne Hospitals NHS Foundation Trust, Barcelona Institute of Science and Technology (BIST), Université Bourgogne Franche-Comté [COMUE] (UBFC), University of Leicester, Plateforme d'information et de services pour les maladies rares et les médicaments orphelins (Orphanet), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Hôpital Broussais-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), EURORDIS-Rare Diseases Europe (Bureau de Paris), EURORDIS - Plateforme Maladies Rares [Paris], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), University Medical Center Groningen [Groningen] (UMCG), European Molecular Biology Laboratory [Hinxton], Universitat de Barcelona (UB), SOLVE-RD Consortium, Projekt DEAL, Unión Europea. Comisión Europea. H2020, European Reference Network for Rare Neurological Diseases (ERN-RND), Haack, T. B., Demidov, G., Sturm, M., Kessler, C., Wayand, M., Wilke, C., Traschutz, A., Schols, L., Hengel, H., Heutink, P., Brunner, H., Scheffer, H., Steyaert, W., Sablauskas, K., Kamsteeg, E. -J., van de Warrenburg, B., van Os, N., te Paske, I., Janssen, E., de Boer, E., Steehouwer, M., Yaldiz, B., Kleefstra, T., Veal, C., Gibson, S., Wadsley, M., Mehtarizadeh, M., Riaz, U., Warren, G., Dizjikan, F. Y., Shorter, T., Straub, V., Bettolo, C. M., Specht, S., Clayton-Smith, J., Banka, S., Alexander, E., Jackson, A., Faivre, L., Thauvin, C., Denomme-Pichon, A. -S., Duffourd, Y., Tisserant, E., Bruel, A. -L., Peyron, C., Pelissier, A., Gut, I. G., Piscia, D., Papakonstantinou, A., Bullich, G., Corvo, A., Garcia, C., Fernandez-Callejo, M., Hernandez, C., Pico, D., Paramonov, I., Lochmuller, H., Bros-Facer, V., Hanauer, M., Olry, A., Lagorce, D., Havrylenko, S., Izem, K., Rigour, F., Stevanin, G., Durr, A., Davoine, C. -S., Guillot-Noel, L., Heinzmann, A., Coarelli, G., Allamand, V., Nelson, I., Yaou, R. B., Metay, C., Eymard, B., Cohen, E., Atalaia, A., Stojkovic, T., Macek, M., Turnovec, M., Thomasova, D., Kremlikova, R. P., Frankova, V., Havlovicova, M., Kremlik, V., Parkinson, H., Keane, T., Senf, A., Robinson, P., Danis, D., Robert, G., Costa, A., Patch, C., Hanna, M., Houlden, H., Reilly, M., Vandrovcova, J., Muntoni, F., Zaharieva, I., Sarkozy, A., Timmerman, V., Baets, J., Van de Vondel, L., Beijer, D., de Jonghe, P., Musacchia, F., Ferlini, A., Selvatici, R., Rossi, R., Neri, M., Aretz, S., Spier, I., Sommer, A. K., Peters, S., Oliveira, C., Pelaez, J. G., Matos, A. R., Jose, C. S., Ferreira, M., Gullo, I., Fernandes, S., Garrido, L., Ferreira, P., Carneiro, F., Swertz, M. A., Johansson, L., van der Velde, J. K., van der Vries, G., Neerincx, P. B., Roelofs-Prins, D., Kohler, S., Metcalfe, A., Drunat, S., Rooryck, C., Trimouille, A., Castello, R., Morleo, M., Pinelli, M., Varavallo, A., De la Paz, M. P., Sanchez, E. B., Martin, E. L., Delgado, B. M., de la Rosa, F. J. A. G., Ciolfi, A., Dallapiccola, B., Pizzi, S., Radio, F. C., Tartaglia, M., Renieri, A., Benetti, E., Balicza, P., Molnar, M. J., Maver, A., Peterlin, B., Munchau, A., Lohmann, K., Herzog, R., Pauly, M., Macaya, A., Marce-Grau, A., Osorio, A. N., de Benito, D. N., Thompson, R., Polavarapu, K., Beeson, D., Cossins, J., Cruz, P. M. R., Hackman, P., Johari, M., Savarese, M., Udd, B., Horvath, R., Capella, G., Valle, L., Holinski-Feder, E., Laner, A., Steinke-Lange, V., Schrock, E., Rump, A., Gestionnaire, HAL Sorbonne Université 5, Centre de Recherche en Myologie, Medicum, University of Helsinki, and Department of Medical and Clinical Genetics
Subjects: Computer science, Consensus Development Conferences as Topic, genetics [Rare Diseases], lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Diseases, Pan european, Tumours of the digestive tract Radboud Institute for Molecular Life Sciences [Radboudumc 14], Exome, Intersectoral Collaboration, Genetics (clinical), Exome sequencing, 0303 health sciences, 030305 genetics & heredity, Medical genetics, 1184 Genetics, developmental biology, physiology, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], 3. Good health, diagnosis [Rare Diseases], Europe, GENOME, Chemistry, New disease, Patient representatives, [SDV.MHEP.AHA] Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], methods [Genetic Testing], MEDLINE, Socio-culturale, 03 medical and health sciences, Viewpoint, Rare Diseases, Exome Sequencing, Genetics, [SDV.MHEP.AHA]Life Sciences [q-bio]/Human health and pathology/Tissues and Organs [q-bio.TO], Humans, ddc:610, Genetic Testing, Biology, 030304 developmental biology, genetics [Genetic Diseases, Inborn], Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Information Dissemination, Genetic Diseases, Inborn, Correction, Data science, diagnosis [Genetic Diseases, Inborn], Data sharing, methods [Exome Sequencing], 3111 Biomedicine, Human medicine, Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19], Rare disease
Abstract: For the first time in Europe hundreds of rare disease (RD) experts team up to actively share and jointly analyse existing patient's data. Solve-RD is a Horizon 2020-supported EU flagship project bringing together >300 clinicians, scientists, and patient representatives of 51 sites from 15 countries. Solve-RD is built upon a core group of four European Reference Networks (ERNs; ERN-ITHACA, ERN-RND, ERN-Euro NMD, ERN-GENTURIS) which annually see more than 270,000 RD patients with respective pathologies. The main ambition is to solve unsolved rare diseases for which a molecular cause is not yet known. This is achieved through an innovative clinical research environment that introduces novel ways to organise expertise and data. Two major approaches are being pursued (i) massive data re-analysis of >19,000 unsolved rare disease patients and (ii) novel combined -omics approaches. The minimum requirement to be eligible for the analysis activities is an inconclusive exome that can be shared with controlled access. The first preliminary data re-analysis has already diagnosed 255 cases form 8393 exomes/genome datasets. This unprecedented degree of collaboration focused on sharing of data and expertise shall identify many new disease genes and enable diagnosis of many so far undiagnosed patients from all over Europe. The Solve-RD project has received funding from the European Union’s Horizon 2020 research and innovation programme under grant agreement No 779257. This research is supported (not financially) by four ERNs: (1) The ERN for Intellectual Disability, Telehealth and Congenital Anomalies (ERN-ITHACA)-Project ID No 869189; (2) The ERN on Rare Neurological Diseases (ERN-RND)-Project ID No 739510; (3) The ERN for Neuromuscular Diseases (ERN Euro-NMD)-Project ID No 870177; (4) The ERN on Genetic Tumour Risk Syndromes (ERN GENTURIS)-Project ID No 739547. The ERNs are co-funded by the European Union within the framework of the Third Health Programme. Open Access funding enabled and organized by Projekt DEAL. Sí
Published: 2021

15. Clinical delineation, sex differences, and genotype-phenotype correlation in pathogenic KDM6A variants causing X-linked Kabuki syndrome type 2

Author: Jonathan Rodgers, Antonia Marchese, Frances Elmslie, Claudine Rieubland, Noriko Miyake, Sophie Julia, Ingrid Scurr, Emmanuel Scalais, Diana S. Johnson, Elise Brischoux-Boucher, Melissa Byler, Lisa Bradley, Julie McGaughran, Siddharth Banka, Maria Gnazzo, Robert Roger Lebel, Stephanie Goh, Damien Lederer, Jane A. Hurst, Maria Cristina Digilio, Ineke van der Burgt, Nobuhiko Okamoto, Mohnish Suri, Víctor Faundes, Rhoda Akilapa, Harinder Gill, Hans T. Bjornsson, Edmond G. Lemire, Saskia Bulk, Katherine Lachlan, Han G. Brunner, Andrew E. Fry, Eric Gershon, Maria Lisa Dentici, Erina Sasaki, Valérie Benoit, Heidre Bezuidenhout, Natalie Canham, Naomichi Matsumoto, Angela F. Brady, Declan Cody, Meriel McEntagart, Seiji Mizuno, and Francesca Romana Lepri
Subjects: Male, 0301 basic medicine, Joint hypermobility, Microcephaly, Hearing loss, 610 Medicine & health, 030105 genetics & heredity, Biology, Article, 03 medical and health sciences, Intellectual Disability, Intellectual disability, medicine, Humans, Missense mutation, Abnormalities, Multiple, Genetic Association Studies, Genetics (clinical), Histone Demethylases, Genetics, Sex Characteristics, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Variant type, Infant, Newborn, medicine.disease, Hematologic Diseases, Phenotype, Neoplasm Proteins, DNA-Binding Proteins, 030104 developmental biology, Vestibular Diseases, Face, Female, medicine.symptom, Kabuki syndrome
Abstract: Contains fulltext : 237823.pdf (Publisher’s version ) (Open Access) PURPOSE: The variant spectrum and the phenotype of X-linked Kabuki syndrome type 2 (KS2) are poorly understood. METHODS: Genetic and clinical details of new and published individuals with pathogenic KDM6A variants were compiled and analyzed. RESULTS: Sixty-one distinct pathogenic KDM6A variants (50 truncating, 11 missense) from 80 patients (34 males, 46 females) were identified. Missense variants clustered in the TRP 2, 3, 7 and Jmj-C domains. Truncating variants were significantly more likely to be de novo. Thirteen individuals had maternally inherited variants and one had a paternally inherited variant. Neonatal feeding difficulties, hypoglycemia, postnatal growth retardation, poor weight gain, motor delay, intellectual disability (ID), microcephaly, congenital heart anomalies, palate defects, renal malformations, strabismus, hearing loss, recurrent infections, hyperinsulinism, seizures, joint hypermobility, and gastroesophageal reflux were frequent clinical findings. Facial features of over a third of patients were not typical for KS. Males were significantly more likely to be born prematurely, have shorter stature, and severe developmental delay/ID. CONCLUSION: We expand the KDM6A variant spectrum and delineate the KS2 phenotype. We demonstrate that the variability of the KS2 phenotypic depends on sex and the variant type. We also highlight the overlaps and differences between the phenotypes of KS2 and KS1.
Published: 2021
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16. Ciliary Dyneins and Dynein Related Ciliopathies

Author: Miriam Schmidts, Han G. Brunner, and Dinu Antony
Subjects: Cytoplasmic Dyneins, QH301-705.5, cilium, short rib polydactyly syndrome, Dynein, primary ciliary dyskinesia, Review, macromolecular substances, Biology, Short Rib-Polydactyly Syndrome, Ciliopathies, 03 medical and health sciences, 0302 clinical medicine, Intraflagellar transport, medicine, Animals, Humans, Cilia, Biology (General), 030304 developmental biology, Primary ciliary dyskinesia, 0303 health sciences, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Polymorphism, Genetic, dynein, intraflagellar transport, Kartagener Syndrome, Cilium, General Medicine, Axonemal Dyneins, medicine.disease, Cell biology, Ciliopathy, Motile cilium, 030217 neurology & neurosurgery
Abstract: Contains fulltext : 237821.pdf (Publisher’s version ) (Open Access) Although ubiquitously present, the relevance of cilia for vertebrate development and health has long been underrated. However, the aberration or dysfunction of ciliary structures or components results in a large heterogeneous group of disorders in mammals, termed ciliopathies. The majority of human ciliopathy cases are caused by malfunction of the ciliary dynein motor activity, powering retrograde intraflagellar transport (enabled by the cytoplasmic dynein-2 complex) or axonemal movement (axonemal dynein complexes). Despite a partially shared evolutionary developmental path and shared ciliary localization, the cytoplasmic dynein-2 and axonemal dynein functions are markedly different: while cytoplasmic dynein-2 complex dysfunction results in an ultra-rare syndromal skeleto-renal phenotype with a high lethality, axonemal dynein dysfunction is associated with a motile cilia dysfunction disorder, primary ciliary dyskinesia (PCD) or Kartagener syndrome, causing recurrent airway infection, degenerative lung disease, laterality defects, and infertility. In this review, we provide an overview of ciliary dynein complex compositions, their functions, clinical disease hallmarks of ciliary dynein disorders, presumed underlying pathomechanisms, and novel developments in the field.
Published: 2021

17. Overarching control of autophagy and DNA damage response by CHD6 revealed by modeling a rare human pathology

Author: Stefan Frank, Yulia Kargapolova, Joanna Brühl, Karim Bouazoune, Rizwan Rehimi, Jonathan Trautwein, Argyris Papantonis, Bernd Wollnik, Alvaro Rada-Iglesias, Bregje W.M. van Bon, Nicole Russ, Magdalena Laugsch, Erwan Watrin, Eduardo G. Gusmao, Hülya Kayserili, Leo Kurian, Christian Gilissen, Konstantinos Sofiadis, Anne Zirkel, Frank J. Kaiser, Han G. Brunner, Gökhan Yigit, Natasa Josipovic, Alexander Hoischen, Peter Nürnberg, Janine Altmüller, Yun Li, Athanasia Mizi, Spiros Palikyras, Gernot Längst, University of Cologne, University Hospital of Cologne [Cologne], Koç University, Philipps Universität Marburg = Philipps University of Marburg, University Medical Center Göttingen (UMG), Radboud University Medical Center [Nijmegen], University of Heidelberg, Medical Faculty, University of Regensburg, Universitätsklinikum Essen [Universität Duisburg-Essen] (Uniklinik Essen), Institut de Génétique et Développement de Rennes (IGDR), Université de Rennes (UR)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Universidad de Cantabria [Santander], Georg-August-University = Georg-August-Universität Göttingen, Deutsche Forschungsgemeinschaft, DFG: 109546710, 2015_A125, 360043781, 397484323, CCRC2407, TRR259, Göttinger Graduiertenschule für Neurowissenschaften, Biophysik und Molekulare Biowissenschaften, GGNB, Uniklinikum Giessen und Marburg, UKGM: 5/2016, Open Access funding enabled and organized by Projekt DEAL., Philipps University of Marburg, Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique )-Centre National de la Recherche Scientifique (CNRS)-Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES), University of Göttingen - Georg-August-Universität Göttingen, German Research Foundation, International Max Planck Research Schools, Projekt DEAL, Karabey Kayserili, Hülya (ORCID 0000-0003-0376-499X & YÖK ID 7945), Kargapolova, Yulia, Rehimi, Rizwan, Bruehl, Joanna, Sofiadis, Konstantinos, Zirkel, Anne, Palikyras, Spiros, Mizi, Athanasia, Li, Yun, Yigit, Gokhan, Hoischen, Alexander, Frank, Stefan, Russ, Nicole, Trautwein, Jonathan, van Bon, Bregje, Gilissen, Christian, Laugsch, Magdalena, Gusmao, Eduardo Gade, Josipovic, Natasa, Altmueller, Janine, Nuernberg, Peter, Laengst, Gernot, Kaiser, Frank J., Watrin, Erwan, Brunner, Han, Rada-Iglesias, Alvaro, Kurian, Leo, Wollnik, Bernd, Bouazoune, Karim, Papantonis, Argyris, and School of Medicine
Subjects: 0301 basic medicine, Epigenomics, [SDV]Life Sciences [q-bio], Hallermann Streiff syndrome, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Medizin, General Physics and Astronomy, Gene Expression, nerve protein, medicine.disease_cause, CHD6 protein, 0302 clinical medicine, Missense mutation, genetics, Science and technology, Gene Editing, Mutation, Multidisciplinary, integumentary system, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Genomics, Chromatin, 3. Good health, Cell biology, enzyme activity, DNA-Binding Proteins, Technology Platforms, autophagy, Protein family, DNA damage, phenotype, Science, Protein structure, Binding domain, Mutations, Gene, Stress, PBAF, Translocation, Phenotypes, SMARCB1, DNA helicase, Nerve Tissue Proteins, Biology, chromatin assembly and disassembly, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, medicine, Autophagy, genomics, Humans, human, Hallermann's Syndrome, chemical binding, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], epigenetics, DNA Helicases, General Chemistry, DNA, DNA binding protein, 030104 developmental biology, physiology, pathology, protein, metabolism, 030217 neurology & neurosurgery
Abstract: © The Author(s) 2021., Members of the chromodomain-helicase-DNA binding (CHD) protein family are chromatin remodelers implicated in human pathologies, with CHD6 being one of its least studied members. We discovered a de novo CHD6 missense mutation in a patient clinically presenting the rare Hallermann-Streiff syndrome (HSS). We used genome editing to generate isogenic iPSC lines and model HSS in relevant cell types. By combining genomics with functional in vivo and in vitro assays, we show that CHD6 binds a cohort of autophagy and stress response genes across cell types. The HSS mutation affects CHD6 protein folding and impairs its ability to recruit co-remodelers in response to DNA damage or autophagy stimulation. This leads to accumulation of DNA damage burden and senescence-like phenotypes. We therefore uncovered a molecular mechanism explaining HSS onset via chromatin control of autophagic flux and genotoxic stress surveillance., This work was supported by UKGM (Project 5/2016), by the Deutsche Forschungsgemeinschaft via TRR81 (Project 109546710) and CCRC2407 (Project 360043781), as well as by an Else-Kroener-Fresenius-Stiftung “Key-Project” grant (Project 2015_A125). Y.K. was further supported by the TRR259 (Project 397484323), and S.P. and N.J. by the International Max Planck Research School for Genome Science, part of the GAUSS/GGNB. Open Access funding enabled and organized by Projekt DEAL.
Published: 2021

18. Germline AGO2 mutations impair RNA interference and human neurological development

Author: Ee-Shien Tan, John Pappas, Tiffany Busa, Marjolein H. Willemsen, Erica H. Gerkes, Astrid Bruckmann, Linda Ramsdell, Davor Lessel, Chieko Chijiwa, Diana Mitter, Ghayda M. Mirzaa, Peter Ian Andrews, Daniela M. Zeitler, Claudia Schob, Pankaj Prasun, M. E. Suzanne Lewis, Rami Abou Jamra, Andriy Kazantsev, Aida Telegrafi, Steffen Syrbe, Chantal Missirian, Victoria Martens, Kimberly Foss, Margot R.F. Reijnders, Bianca Panis, Ilaria Mannucci, Bernarda Lozić, Fatemeh Hassani Nia, Rolph Pfundt, Tanja Kovacevic, Han G. Brunner, Christian Kubisch, Allyn McConkie-Rosell, Breana Cham, Gunter Meister, Jessika Johannsen, Veronika Graus, Henny H. Lemmink, Stefan Kindler, Jonas Denecke, Kirsty McWalter, Ivana Lessel, Zoya Ignatova, Hans-Jürgen Kreienkamp, Matthew Osmond, Thatjana Gardeitchik, Alexander P.A. Stegmann, Rachel Rabin, Alexander Bartholomäus, Jérémie Mortreux, Katharina Löhner, Tony Roscioli, Tjitske Kleefstra, Taila Hartley, Andreas Merkenschlager, Patrick Rump, Marie T. McDonald, Kym M. Boycott, Evelien Zonneveld-Huijssoon, David A. Dyment, Carey-Anne Evans, Margje Sinnema, Sabine Lüttgen, Joanna Lazier, Diana Le Duc, Kerith-Rae Dias, Ene-Choo Tan, Marseille medical genetics - Centre de génétique médicale de Marseille (MMG), Aix Marseille Université (AMU)-Institut National de la Santé et de la Recherche Médicale (INSERM), Département de génétique médicale [Hôpital de la Timone - APHM], Aix Marseille Université (AMU)-Assistance Publique - Hôpitaux de Marseille (APHM)- Hôpital de la Timone [CHU - APHM] (TIMONE)-Institut National de la Santé et de la Recherche Médicale (INSERM), ANR-17-CE16-0025,MicroRNAct,Identification de complexes microARN/mARN fonctionnels dans le cerveau antérieur de souris: de la neurogenèse au comportement et à la pathologie(2017), MUMC+: DA KG Polikliniek (9), and RS: FHML non-thematic output
Subjects: 0301 basic medicine, INTELLECTUAL DISABILITY, MICRORNAS, [SDV]Life Sciences [q-bio], molecular-dynamics, General Physics and Astronomy, ARGONAUTE-2, ARGONAUTE-2, Hippocampus, Nervous System, Transcriptome, Mice, 0302 clinical medicine, RNA interference, Cluster Analysis, Phosphorylation, RNA, Small Interfering, lcsh:Science, Child, Regulation of gene expression, Neurons, Multidisciplinary, Molecular medicine, Neurodevelopmental disorders, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], 3. Good health, Cell biology, Child, Preschool, Argonaute Proteins, RNA Interference, STRUCTURAL BASIS, Adolescent, Science, Biology, Molecular Dynamics Simulation, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, Protein Domains, microRNA, Gene silencing, Animals, Humans, RNA-Induced Silencing Complex, Gene Silencing, RNA, Messenger, Messenger RNA, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], CLEAVAGE, HEK 293 cells, RECOGNITION, crystal-structure, RNA, General Chemistry, Dendrites, Fibroblasts, GENE, Rats, 030104 developmental biology, Germ Cells, HEK293 Cells, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Mutation, lcsh:Q, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, 030217 neurology & neurosurgery
Abstract: ARGONAUTE-2 and associated miRNAs form the RNA-induced silencing complex (RISC), which targets mRNAs for translational silencing and degradation as part of the RNA interference pathway. Despite the essential nature of this process for cellular function, there is little information on the role of RISC components in human development and organ function. We identify 13 heterozygous mutations in AGO2 in 21 patients affected by disturbances in neurological development. Each of the identified single amino acid mutations result in impaired shRNA-mediated silencing. We observe either impaired RISC formation or increased binding of AGO2 to mRNA targets as mutation specific functional consequences. The latter is supported by decreased phosphorylation of a C-terminal serine cluster involved in mRNA target release, increased formation of dendritic P-bodies in neurons and global transcriptome alterations in patient-derived primary fibroblasts. Our data emphasize the importance of gene expression regulation through the dynamic AGO2-RNA association for human neuronal development., AGO2 binds to miRNAs to repress expression of cognate target mRNAs. Here the authors report that heterozygous AGO2 mutations result in defects in neurological development and impair RNA interference.
Published: 2020

19. Brunner syndrome associated MAOA dysfunction in human dopaminergic neurons results in NMDAR hyperfunction and increased network activity

Author: Britt Mossink, Elizabeth E. Palmer, Marina Hakobjan, Barbara Franke, Maren Bormann, Jon-Ruben van Rhijn, Yan Shi, Monica Frega, Chantal Schoenmaker, Nael Nadif Kasri, Han G. Brunner, Sarah Kittel-Schneider, Dirk Schubert, Teun M. Klein Gunnewiek, Hatice Recaioglu, and Laurence Faivre
Subjects: Brunner syndrome, Dopaminergic, Biology, medicine.disease, Norepinephrine, Monoamine neurotransmitter, Dopamine, biology.protein, medicine, GRIN2B, Serotonin, Monoamine oxidase A, Neuroscience, medicine.drug
Abstract: BackgroundMonoamine neurotransmitter abundance affects motor control, emotion, and cognitive function and is regulated by monoamine oxidases. Amongst these, monoamine oxidase A (MAOA) catalyzes the degradation of dopamine, norepinephrine, and serotonin into their inactive metabolites. Loss-of-function mutations in the X-linked MAOA gene cause Brunner syndrome, which is characterized by various forms of impulsivity, maladaptive externalizing behavior, and mild intellectual disability. Impaired MAOA activity in individuals with Brunner syndrome results in bioamine aberration, but it is currently unknown how this affects neuronal function.MethodsWe generated human induced pluripotent stem cell (hiPSC)-derived dopaminergic (DA) neurons from three individuals with Brunner syndrome carrying different mutations, and used CRISPR/Cas9 mediated homologous recombination to rescue MAOA function. We used these lines to characterize morphological and functional properties of DA neuronal cultures at the single cell and neuronal network level in vitro.ResultsBrunner syndrome DA neurons showed reduced synaptic density but hyperactive network activity. Intrinsic functional properties and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR)-mediated synaptic transmission were not affected by MAOA dysfunction. Instead, we show that the neuronal network hyperactivity is mediated by upregulation of the GRIN2A and GRIN2B subunits of the N-methyl-D-aspartate receptor (NMDAR), and rescue of MAOA results in normalization of NMDAR function as well as restoration of network activity.ConclusionsOur data suggest that MAOA dysfunction in Brunner syndrome increases activity of dopaminergic neurons through upregulation of NMDAR function, which may contribute to Brunner syndrome associated phenotypes.
Published: 2020

20. Distinct Cardiac Transcriptomic Clustering in Titin and Lamin A/C-Associated Dilated Cardiomyopathy Patients

Author: Ingrid P.C. Krapels, Emma L. Robinson, Kasper W.J. Derks, Stephane Heymans, Job A J Verdonschot, Arthur van den Wijngaard, Ping Wang, Mark R. Hazebroek, Michiel E. Adriaens, Han G. Brunner, RS: Carim - H02 Cardiomyopathy, Cardiologie, Genetica & Celbiologie, MUMC+: DA KG Lab Centraal Lab (9), MUMC+: MA Med Staf Artsass Cardiologie (9), Maastricht Centre for Systems Biology, RS: FSE MaCSBio, RS: FPN MaCSBio, RS: FHML MaCSBio, MUMC+: DA KG Polikliniek (9), MUMC+: DA Klinische Genetica (5), Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, and MUMC+: MA Med Staf Spec Cardiologie (9)
Subjects: Cardiomyopathy, Dilated, Male, sequence analysis, Sequence analysis, phenotype, principal component analysis, genotype, Cardiomyopathy, Transcriptome, Physiology (medical), Genotype, medicine, Humans, Connectin, Genetics, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], biology, business.industry, Gene Expression Profiling, Dilated cardiomyopathy, medicine.disease, Lamin Type A, Phenotype, biology.protein, RNA, Titin, Female, Cardiology and Cardiovascular Medicine, business, cardiomyopathy, dilated, Lamin
Abstract: Contains fulltext : 225426.pdf (Publisher’s version ) (Open Access)
Published: 2020

21. Overarching control of autophagy and DNA damage response by CHD6 revealed by modeling a rare human pathology

Author: Stefan Frank, Goekhan Yigit, Erwan Watrin, Hulya Kayserli, Alexander Hoischen, Rizwan Rehimi, Eduardo G. Gusmao, Bernd Wollnik, Janine Altmeuller, Yul Li, Yulia Kargapolova, Anne Zirkel, Leo Kurian, Peter Nuernberg, Joanna Bruehl, Gernot Laengst, Magdalena Laugsch, Han G. Brunner, Jonathan Trautwein, Frank J. Kaiser, Natasa Josipovic, Argyris Papantonis, Karim Bouazoune, Alvaro Rada-Iglesias, and Nicole Russ
Subjects: 0303 health sciences, Cell type, integumentary system, Protein family, DNA damage, Autophagy, Genomics, Biology, Phenotype, 3. Good health, Cell biology, Chromatin, 03 medical and health sciences, 0302 clinical medicine, Gene, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: Members of the chromodomain-helicase-DNA binding (CHD) protein family are chromatin remodelers critically implicated in human pathologies, with CHD6 being one of its least studied members. Here, we discovered a de novo CHD6 missense mutation in a patient clinically presenting the rare Hallermann-Streiff syndrome (HSS). We used genome editing to generate isogenic iPSC lines and model HSS in relevant cell types. We show that CHD6 binds a cohort of autophagy and stress response genes across cell types. The HSS-mutation affects CHD6 protein folding and impairs its ability to recruit co-factors in response to DNA damage or autophagy stimulation. This leads to an accumulation of DNA damage burden and to senescence-like phenotypes. By combining genomics and functional assays, we describe for the first time a molecular mechanism for the chromatin control of autophagic flux and genotoxic stress surveillance that applies broadly to human cell types and explains HSS onset.
Published: 2020

22. A mutation update for the FLNC gene in myopathies and cardiomyopathies

Author: Arthur van den Wijngaard, Carlo Marcelis, Ingrid P.C. Krapels, Yvonne M. Hoedemaekers, Apollonia T. J. M. Helderman-van den Enden, Debby M.E.I. Hellebrekers, Job A J Verdonschot, Esther Brusse, Godelieve R.F. Claes, Hanne M Boen, Imke Christiaans, Janneke G. J. Hoeijmakers, Marlies Kempers, Pieter Koopman, Bart Loeys, Han G. Brunner, Stephane Heymans, Els K. Vanhoutte, Amber de Haan, Jaap I. van Waning, Ronald H. Lekanne Deprez, Annette F. Baas, Dennis Dooijes, Emeline M. Van Craenenbroeck, Daniela Q.C.M. Barge-Schaapveld, Folkert W. Asselbergs, Asselbergs, Folkert/0000-0002-1692-8669, Koopman, Pieter/0000-0002-6373-180X, Christiaans, Imke/0000-0001-5799-2344, Cardiologie, RS: Carim - H02 Cardiomyopathy, MUMC+: DA KG Polikliniek (9), MUMC+: DA KG Lab Centraal Lab (9), MUMC+: MA Med Staf Spec Neurologie (9), RS: MHeNs - R1 - Cognitive Neuropsychiatry and Clinical Neuroscience, MUMC+: MA Med Staf Spec Cardiologie (9), MUMC+: DA Klinische Genetica (5), Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, Human Genetics, ACS - Heart failure & arrhythmias, ACS - Pulmonary hypertension & thrombosis, and ARD - Amsterdam Reproduction and Development
Subjects: Cardiomyopathy, Filamin, MYOFIBRILLAR MYOPATHY, Missense mutation, FLNC, Muscular dystrophy, Genetics (clinical), Genetics & Heredity, Genetics, 0303 health sciences, Mutation Update, HYPERTROPHIC CARDIOMYOPATHY, 030305 genetics & heredity, Hypertrophic cardiomyopathy, genotype–phenotype correlation, filamin, cardiovascular system, HEART-FAILURE, medicine.symptom, Cardiomyopathies, Haploinsufficiency, PROTEIN AGGREGATION, Life Sciences & Biomedicine, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Myopathies, Structural, Congenital, myopathy, Cardiomyopathy, Dilated, TRUNCATING VARIANTS, FILAMIN-C, Filamins, ACTIN-BINDING DOMAIN, Biology, genotype-phenotype correlation, CLASSIFICATION, 03 medical and health sciences, Muscular Diseases, medicine, Animals, Humans, cardiovascular diseases, Myopathy, Genetic Association Studies, 030304 developmental biology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Science & Technology, IDENTIFICATION, Arrhythmias, Cardiac, medicine.disease, MUSCULAR-DYSTROPHY, Disease Models, Animal, Mutation, Human medicine, cardiomyopathy
Abstract: Filamin C (FLNC) variants are associated with cardiac and muscular phenotypes. Originally, FLNC variants were described in myofibrillar myopathy (MFM) patients. Later, high‐throughput screening in cardiomyopathy cohorts determined a prominent role for FLNC in isolated hypertrophic and dilated cardiomyopathies (HCM and DCM). FLNC variants are now among the more prevalent causes of genetic DCM. FLNC‐associated DCM is associated with a malignant clinical course and a high risk of sudden cardiac death. The clinical spectrum of FLNC suggests different pathomechanisms related to variant types and their location in the gene. The appropriate functioning of FLNC is crucial for structural integrity and cell signaling of the sarcomere. The secondary protein structure of FLNC is critical to ensure this function. Truncating variants with subsequent haploinsufficiency are associated with DCM and cardiac arrhythmias. Interference with the dimerization and folding of the protein leads to aggregate formation detrimental for muscle function, as found in HCM and MFM. Variants associated with HCM are predominantly missense variants, which cluster in the ROD2 domain. This domain is important for binding to the sarcomere and to ensure appropriate cell signaling. We here review FLNC genotype–phenotype correlations based on available evidence., The location of causative variants leading to the filaminopathies A are mapped onto FLNA protein monomers. Variants leading to ‘loss‐of‐function’ disorders (left monomer) and ‘gain‐of‐function’ disorders (right monomer) can clearly be seen to cluster. ‘Hotspot’ regions are marked with larger symbols. PH: periventricular heterotopia, CIPX: congenital intestinal pseudo‐obstruction, IMT: isolated macrothrombocytopenia, FCMPD: familial cardiac myxomatous polyvalvular dystrophy, OPD: otopalatodigital syndrome, FMD: frontometaphyseal dysplasia, CKCO: condition comprising contractures, keloid, cardiac defects and optic anomalies, MNS: Melnick‐Needles syndrome, DCD: digitocutaneous dysplasia, ABD: actin‐binding domain, CHD: calponin homology domain, H: hinge.
Published: 2020

23. Genetic correlations and genome-wide associations of cortical structure in general population samples of 22,824 adults

Author: Hofer, Edith, Roshchupkin, Gennady V, Bernard, Manon, Grasby, Katrina L, Jahanshad, Neda, Painter, Jodie N, Colodro-Conde, Lucía, Bralten, Janita, Hibar, Derrek P, Lind, Penelope A, Pizzagalli, Fabrizio, Ching, Christopher R K, McMahon, Mary Agnes B, Bis, Joshua C, Shatokhina, Natalia, Zsembik, Leo C P, Agartz, Ingrid, Alhusaini, Saud, Almeida, Marcio A A, Alnæs, Dag, Amlien, Inge K, Andersson, Micael, Ard, Tyler, Armstrong, Nicola J, Gillespie, Nathan A, Ashley-Koch, Allison, Brouwer, Rachel M, Buimer, Elizabeth E L, Bülow, Robin, Bürger, Christian, Cannon, Dara M, Chakravarty, Mallar, Chen, Qiang, Cheung, Joshua W, Luciano, Michelle, Couvy-Duchesne, Baptiste, Dale, Anders M, Dalvie, Shareefa, de Araujo, Tânia K, de Zubicaray, Greig I, de Zwarte, Sonja M C, den Braber, Anouk, Doan, Nhat Trung, Dohm, Katharina, Ehrlich, Stefan, Mishra, Aniket, Engelbrecht, Hannah-Ruth, Erk, Susanne, Fan, Chun Chieh, Fedko, Iryna O, Foley, Sonya F, Ford, Judith M, Fukunaga, Masaki, Garrett, Melanie E, Ge, Tian, Giddaluru, Sudheer, Scholz, Markus, Goldman, Aaron L, Groenewold, Nynke A, Grotegerd, Dominik, Gurholt, Tiril P, Gutman, Boris A, Hansell, Narelle K, Harris, Mathew A, Harrison, Marc B, Haswell, Courtney C, Hauser, Michael, Teumer, Alexander, Herms, Stefan, Heslenfeld, Dirk J, Ho, New Fei, Hoehn, David, Hoffmann, Per, Holleran, Laurena, Hoogman, Martine, Hottenga, Jouke-Jan, Ikeda, Masashi, Janowitz, Deborah, Xia, Rui, Jansen, Iris E, Jia, Tianye, Jockwitz, Christiane, Kanai, Ryota, Karama, Sherif, Kasperaviciute, Dalia, Kaufmann, Tobias, Kelly, Sinead, Kikuchi, Masataka, Klein, Marieke, Jian, Xueqiu, Knapp, Michael, Knodt, Annchen R, Krämer, Bernd, Lam, Max, Lancaster, Thomas M, Lee, Phil H, Lett, Tristram A, Lewis, Lindsay B, Lopes-Cendes, Iscia, Mosley, Thomas H, Macciardi, Fabio, Marquand, Andre F, Mathias, Samuel R, Melzer, Tracy R, Milaneschi, Yuri, Mirza-Schreiber, Nazanin, Moreira, Jose C V, Mühleisen, Thomas W, Müller-Myhsok, Bertram, Najt, Pablo, Adams, Hieab H H, Saba, Yasaman, Nakahara, Soichiro, Nho, Kwangsik, Olde Loohuis, Loes M, Orfanos, Dimitri Papadopoulos, Pearson, John F, Pitcher, Toni L, Pütz, Benno, Ragothaman, Anjanibhargavi, Rashid, Faisal M, Redlich, Ronny, Pirpamer, Lukas, Reinbold, Céline S, Repple, Jonathan, Richard, Geneviève, Riedel, Brandalyn C, Risacher, Shannon L, Rocha, Cristiane S, Mota, Nina Roth, Salminen, Lauren, Saremi, Arvin, Saykin, Andrew J, Seiler, Stephan, Schlag, Fenja, Schmaal, Lianne, Schofield, Peter R, Secolin, Rodrigo, Shapland, Chin Yang, Shen, Li, Shin, Jean, Shumskaya, Elena, Sønderby, Ida E, Sprooten, Emma, Becker, James T, Strike, Lachlan T, Tansey, Katherine E, Thalamuthu, Anbupalam, Thomopoulos, Sophia I, Tordesillas-Gutiérrez, Diana, Turner, Jessica A, Uhlmann, Anne, Vallerga, Costanza Ludovica, van der Meer, Dennis, Carmichael, Owen, van Donkelaar, Marjolein M J, van Eijk, Liza, van Erp, Theo G M, van Haren, Neeltje E M, van Rooij, Daan, van Tol, Marie-José, Veldink, Jan H, Verhoef, Ellen, Walton, Esther, Wang, Mingyuan, Rotter, Jerome I, Wang, Yunpeng, Wardlaw, Joanna M, Wen, Wei, Westlye, Lars T, Whelan, Christopher D, Witt, Stephanie H, Wittfeld, Katharina, Wolf, Christiane, Wolfers, Thomas, Yasuda, Clarissa L, Psaty, Bruce M, Zaremba, Dario, Zhang, Zuo, Zhu, Alyssa H, Zwiers, Marcel P, Artiges, Eric, Assareh, Amelia A, Ayesa-Arriola, Rosa, Belger, Aysenil, Brandt, Christine L, Brown, Gregory G, Lopez, Oscar L, Cichon, Sven, Curran, Joanne E, Davies, Gareth E, Degenhardt, Franziska, Dietsche, Bruno, Djurovic, Srdjan, Doherty, Colin P, Espiritu, Ryan, Garijo, Daniel, Gil, Yolanda, Amin, Najaf, Gowland, Penny A, Green, Robert C, Häusler, Alexander N, Heindel, Walter, Ho, Beng-Choon, Hoffmann, Wolfgang U, Holsboer, Florian, Homuth, Georg, Hosten, Norbert, Jack, Clifford R, van der Lee, Sven J, Jang, MiHyun, Jansen, Andreas, Kolskår, Knut, Koops, Sanne, Krug, Axel, Lim, Kelvin O, Luykx, Jurjen J, Mathalon, Daniel H, Mather, Karen A, Mattay, Venkata S, Knol, Maria J, Yang, Qiong, Matthews, Sarah, Son, Jaqueline Mayoral Van, McEwen, Sarah C, Melle, Ingrid, Morris, Derek W, Mueller, Bryon A, Nauck, Matthias, Nordvik, Jan E, Nöthen, Markus M, O'Leary, Daniel S, Himali, Jayandra J, Opel, Nils, Martinot, Marie -Laure Paillère, Pike, G Bruce, Preda, Adrian, Quinlan, Erin B, Ratnakar, Varun, Reppermund, Simone, Steen, Vidar M, Torres, Fábio R, Veltman, Dick J, Maillard, Pauline, Voyvodic, James T, Whelan, Robert, White, Tonya, Yamamori, Hidenaga, Alvim, Marina K M, Ames, David, Anderson, Tim J, Andreassen, Ole A, Arias-Vasquez, Alejandro, Bastin, Mark E, Beiser, Alexa S, Baune, Bernhard T, Blangero, John, Boomsma, Dorret I, Brodaty, Henry, Brunner, Han G, Buckner, Randy L, Buitelaar, Jan K, Bustillo, Juan R, Cahn, Wiepke, Calhoun, Vince, DeCarli, Charles, Caseras, Xavier, Caspers, Svenja, Cavalleri, Gianpiero L, Cendes, Fernando, Corvin, Aiden, Crespo-Facorro, Benedicto, Dalrymple-Alford, John C, Dannlowski, Udo, de Geus, Eco J C, Deary, Ian J, Delanty, Norman, Depondt, Chantal, Desrivières, Sylvane, Donohoe, Gary, Espeseth, Thomas, Fernández, Guillén, Fisher, Simon E, Flor, Herta, Forstner, Andreas J, Francks, Clyde, Lewis, Lindsay, Franke, Barbara, Glahn, David C, Gollub, Randy L, Grabe, Hans J, Gruber, Oliver, Håberg, Asta K, Hariri, Ahmad R, Hartman, Catharina A, Hashimoto, Ryota, Heinz, Andreas, Harris, Mat, Hillegers, Manon H J, Hoekstra, Pieter J, Holmes, Avram J, Hong, L Elliot, Hopkins, William D, Hulshoff Pol, Hilleke E, Jernigan, Terry L, Jönsson, Erik G, Kahn, René S, Kennedy, Martin A, Kircher, Tilo T J, Kochunov, Peter, Kwok, John B J, Hellard, Stephanie Le, Martin, Nicholas G, Martinot, Jean -Luc, McDonald, Colm, McMahon, Katie L, Meyer-Lindenberg, Andreas, Morey, Rajendra A, Nyberg, Lars, Oosterlaan, Jaap, Ophoff, Roel A, Paus, Tomáš, Pausova, Zdenka, Penninx, Brenda W J H, Polderman, Tinca J C, Posthuma, Danielle, Rietschel, Marcella, Roffman, Joshua L, Lin, Honghuang, Veronica Witte, A., Rowland, Laura M, Sachdev, Perminder S, Sämann, Philipp G, Schumann, Gunter, Sim, Kang, Sisodiya, Sanjay M, Smoller, Jordan W, Sommer, Iris E, Pourcain, Beate St, Stein, Dan J, Beyer, Frauke, Toga, Arthur W, Trollor, Julian N, Van der Wee, Nic J A, van 't Ent, Dennis, Völzke, Henry, Walter, Henrik, Weber, Bernd, Weinberger, Daniel R, Wright, Margaret J, Zhou, Juan, Loeffler, Markus, Stein, Jason L, Thompson, Paul M, Medland, Sarah E, Kwok, John B, Trollor, Julian, Li, Shuo, Jiang, Jiyang, Vernooij, Meike W, Hofman, Albert, Uitterlinden, André G, Niessen, Wiro J, Völker, Uwe, Zare, Habil, Bruce Pike, G., Maingault, Sophie, Crivello, Fabrice, Tzourio, Christophe, Amouyel, Philippe, Mazoyer, Bernard, Neale, Michael C, Franz, Carol E, Lyons, Michael J, Ahmad, Shahzad, Panizzon, Matthew S, Logue, Mark, consortium, ENIGMA, Kremen, William S, Villringer, Arno, Satizabal, Claudia L, van Duijn, Cornelia M, Grabe, Hans, Longstreth, William T, Fornage, Myriam, Paus, Tomas, Debette, Stephanie, Ikram, M Arfan, Schmidt, Helena, Schmidt, Reinhold, Seshadri, Sudha, University of Graz, Medical University Graz, Erasmus University Medical Center [Rotterdam] (Erasmus MC), Boston University School of Medicine (BUSM), Boston University [Boston] (BU), School of Public Health [Boston], University of Texas Health Science Center, The University of Texas Health Science Center at Houston (UTHealth), The University of Texas at San Antonio (UTSA), Murdoch University, The Hospital for sick children [Toronto] (SickKids), University of Washington [Seattle], Virginia Commonwealth University (VCU), QIMR Berghofer Medical Research Institute, University of Edinburgh, Bordeaux population health (BPH), Université de Bordeaux (UB)-Institut de Santé Publique, d'Épidémiologie et de Développement (ISPED)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universität Leipzig [Leipzig], Universität Greifswald - University of Greifswald, University of Mississippi Medical Center (UMMC), University of California [Davis] (UC Davis), University of California, University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), Pennington Biomedical Research Center, Louisiana State University (LSU), Los Angeles Biomedical Research Institute (LA BioMed), McGill University = Université McGill [Montréal, Canada], Max Planck Institute for Human Cognitive and Brain Sciences [Leipzig] (IMPNSC), Max-Planck-Gesellschaft, University of New South Wales [Sydney] (UNSW), Neuroscience Research Australia (NeuRA), The University of Sydney, University of Queensland [Brisbane], The Royal Melbourne Hospital, University of Melbourne, Harvard T.H. Chan School of Public Health, Delft University of Technology (TU Delft), German Research Center for Neurodegenerative Diseases - Deutsches Zentrum für Neurodegenerative Erkrankungen (DZNE), University of Toronto, University of Calgary, Institut des Maladies Neurodégénératives [Bordeaux] (IMN), Université de Bordeaux (UB)-Centre National de la Recherche Scientifique (CNRS), CHU Bordeaux [Bordeaux], Facteurs de Risque et Déterminants Moléculaires des Maladies liées au Vieillissement - U 1167 (RID-AGE), Institut Pasteur de Lille, Réseau International des Instituts Pasteur (RIIP)-Réseau International des Instituts Pasteur (RIIP)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Lille-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Réseau International des Instituts Pasteur (RIIP), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University of California [San Diego] (UC San Diego), University of Oslo (UiO), Oslo University Hospital [Oslo], VA Boston Healthcare System, University of Southern California (USC), Radboud University Medical Center [Nijmegen], Radboud university [Nijmegen], Janssen Research & Development, University of North Carolina [Chapel Hill] (UNC), University of North Carolina System (UNC), Prince of Wales Hospital, University Hospital Leipzig, University of Oxford [Oxford], Holland Bloorview Kids Rehabilitation Hospital [Toronto, ON, Canada], Epidemiology, Medical Informatics, Radiology & Nuclear Medicine, Neurology, Complex Trait Genetics, Biological Psychology, Cognitive Psychology, IBBA, APH - Health Behaviors & Chronic Diseases, APH - Personalized Medicine, APH - Mental Health, APH - Methodology, Clinical Neuropsychology, Clinical Developmental Psychology, Amsterdam Neuroscience - Complex Trait Genetics, Movement Disorder (MD), Clinical Cognitive Neuropsychiatry Research Program (CCNP), General Paediatrics, ARD - Amsterdam Reproduction and Development, Karl-Franzens-Universität Graz, Universität Leipzig, University of California (UC), Radboud University [Nijmegen], University of Oxford, Psychiatry, Anatomy and neurosciences, Pediatric surgery, Human genetics, APH - Digital Health, and Karl-Franzens-Universität [Graz, Autriche]
Subjects: 0301 basic medicine, Male, Genetics of the nervous system, Aging, General Physics and Astronomy, Genome-wide association study, Disease, VARIANTS, genetics [Mental Disorders], Genome-wide association studies, 0302 clinical medicine, Cognition, PARKINSONS-DISEASE, SCHIZOPHRENIA, 80 and over, 2.1 Biological and endogenous factors, Aetiology, lcsh:Science, Aged, 80 and over, education.field_of_study, Multidisciplinary, ENIGMA consortium, Mental Disorders, Brain, Neurodegenerative Diseases, Genomics, Single Nucleotide, Middle Aged, Biobank, ALZHEIMERS-DISEASE, Phenotype, VINTAGE, Neurology, Chromosome Structures, Schizophrenia, genetics [Aging], Neurological, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, ddc:500, Biotechnology, Adult, Science, geentics of the nervous system, 1.1 Normal biological development and functioning, Population, SURFACE-AREA, ORGANIZATION, Biology, Polymorphism, Single Nucleotide, General Biochemistry, Genetics and Molecular Biology, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Underpinning research, THICKNESS, medicine, Genetics, Humans, Polymorphism, education, HEALTHY, METAANALYSIS, Aged, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], [SDV.GEN.GPO]Life Sciences [q-bio]/Genetics/Populations and Evolution [q-bio.PE], Genetic heterogeneity, neurology, Human Genome, Neurosciences, General Chemistry, Heritability, medicine.disease, Brain Disorders, INDIVIDUALS, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Evolutionary biology, genetics [Neurodegenerative Diseases], VOLUME, genome-wide association studies, lcsh:Q, 030217 neurology & neurosurgery, Genome-Wide Association Study
Abstract: Cortical thickness, surface area and volumes vary with age and cognitive function, and in neurological and psychiatric diseases. Here we report heritability, genetic correlations and genome-wide associations of these cortical measures across the whole cortex, and in 34 anatomically predefined regions. Our discovery sample comprises 22,824 individuals from 20 cohorts within the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank. We identify genetic heterogeneity between cortical measures and brain regions, and 160 genome-wide significant associations pointing to wnt/β-catenin, TGF-β and sonic hedgehog pathways. There is enrichment for genes involved in anthropometric traits, hindbrain development, vascular and neurodegenerative disease and psychiatric conditions. These data are a rich resource for studies of the biological mechanisms behind cortical development and aging., Cortex morphology varies with age, cognitive function, and in neurological and psychiatric diseases. Here the authors report 160 genome-wide significant associations with thickness, surface area and volume of the total cortex and 34 cortical regions from a GWAS meta-analysis in 22,824 adults.
Published: 2020

24. The genetic architecture of the human cerebral cortex

Author: Grasby, Katrina L, Jahanshad, Neda, Shatokhina, Natalia, Mirza-Schreiber, Nazanin, Moreira, Jose C V, Mühleisen, Thomas W, Müller-Myhsok, Bertram, Najt, Pablo, Nakahara, Soichiro, Nho, Kwangsik, Olde Loohuis, Loes M, Orfanos, Dimitri Papadopoulos, Pearson, John F, Zsembik, Leo C P, Pitcher, Toni L, Pütz, Benno, Quidé, Yann, Ragothaman, Anjanibhargavi, Rashid, Faisal M, Reay, William R, Redlich, Ronny, Reinbold, Céline S, Repple, Jonathan, Richard, Geneviève, Thomopoulos, Sophia I, Riedel, Brandalyn C, Risacher, Shannon L, Rocha, Cristiane S, Mota, Nina Roth, Salminen, Lauren, Saremi, Arvin, Saykin, Andrew J, Schlag, Fenja, Schmaal, Lianne, Schofield, Peter R, Zhu, Alyssa H, Secolin, Rodrigo, Shapland, Chin Yang, Shen, Li, Shin, Jean, Shumskaya, Elena, Sønderby, Ida E, Sprooten, Emma, Tansey, Katherine E, Teumer, Alexander, Thalamuthu, Anbupalam, Strike, Lachlan T, Tordesillas-Gutiérrez, Diana, Turner, Jessica A, Uhlmann, Anne, Vallerga, Costanza Ludovica, van der Meer, Dennis, van Donkelaar, Marjolein M J, van Eijk, Liza, van Erp, Theo G M, van Haren, Neeltje E M, van Rooij, Daan, Agartz, Ingrid, van Tol, Marie-José, Veldink, Jan H, Verhoef, Ellen, Walton, Esther, Wang, Mingyuan, Wang, Yunpeng, Wardlaw, Joanna M, Wen, Wei, Westlye, Lars T, Whelan, Christopher D, Alhusaini, Saud, Witt, Stephanie H, Wittfeld, Katharina, Wolf, Christiane, Wolfers, Thomas, Wu, Jing Qin, Yasuda, Clarissa L, Zaremba, Dario, Zhang, Zuo, Zwiers, Marcel P, Artiges, Eric, Almeida, Marcio A A, Assareh, Amelia A, Ayesa-Arriola, Rosa, Belger, Aysenil, Brandt, Christine L, Brown, Gregory G, Cichon, Sven, Curran, Joanne E, Davies, Gareth E, Degenhardt, Franziska, Dennis, Michelle F, Alnæs, Dag, Dietsche, Bruno, Djurovic, Srdjan, Doherty, Colin P, Espiritu, Ryan, Garijo, Daniel, Gil, Yolanda, Gowland, Penny A, Green, Robert C, Häusler, Alexander N, Heindel, Walter, Amlien, Inge K, Ho, Beng-Choon, Hoffmann, Wolfgang U, Holsboer, Florian, Homuth, Georg, Hosten, Norbert, Jack, Clifford R, Jang, MiHyun, Jansen, Andreas, Kimbrel, Nathan A, Kolskår, Knut, Painter, Jodie N, Andersson, Micael, Koops, Sanne, Krug, Axel, Lim, Kelvin O, Luykx, Jurjen J, Mathalon, Daniel H, Mather, Karen A, Mattay, Venkata S, Matthews, Sarah, Mayoral Van Son, Jaqueline, McEwen, Sarah C, Ard, Tyler, Melle, Ingrid, Morris, Derek W, Mueller, Bryon A, Nauck, Matthias, Nordvik, Jan E, Nöthen, Markus M, O'Leary, Daniel S, Opel, Nils, Martinot, Marie-Laure Paillère, Pike, G Bruce, Armstrong, Nicola J, Preda, Adrian, Quinlan, Erin B, Rasser, Paul E, Ratnakar, Varun, Reppermund, Simone, Steen, Vidar M, Tooney, Paul A, Torres, Fábio R, Veltman, Dick J, Voyvodic, James T, Ashley-Koch, Allison, Whelan, Robert, White, Tonya, Yamamori, Hidenaga, Adams, Hieab H H, Bis, Joshua C, Debette, Stephanie, Decarli, Charles, Fornage, Myriam, Gudnason, Vilmundur, Hofer, Edith, Atkins, Joshua R, Ikram, M Arfan, Launer, Lenore, Longstreth, W. T., Lopez, Oscar L, Mazoyer, Bernard, Mosley, Thomas H, Roshchupkin, Gennady V, Satizabal, Claudia L, Schmidt, Reinhold, Seshadri, Sudha, Bernard, Manon, Yang, Qiong, Initiative, Alzheimer’s Disease Neuroimaging, Consortium, CHARGE, Consortium, EPIGEN, Consortium, IMAGEN, Consortium, SYS, Initiative, Parkinson’s Progression Markers, Alvim, Marina K M, Ames, David, Anderson, Tim J, Brouwer, Rachel M, Andreassen, Ole A, Arias-Vasquez, Alejandro, Bastin, Mark E, Baune, Bernhard T, Beckham, Jean C, Blangero, John, Boomsma, Dorret I, Brodaty, Henry, Brunner, Han G, Buckner, Randy L, Buimer, Elizabeth E L, Buitelaar, Jan K, Bustillo, Juan R, Cahn, Wiepke, Cairns, Murray J, Calhoun, Vince, Carr, Vaughan J, Caseras, Xavier, Caspers, Svenja, Cavalleri, Gianpiero L, Cendes, Fernando, Bülow, Robin, Corvin, Aiden, Crespo-Facorro, Benedicto, Dalrymple-Alford, John C, Dannlowski, Udo, de Geus, Eco J C, Deary, Ian J, Delanty, Norman, Depondt, Chantal, Desrivières, Sylvane, Donohoe, Gary, Bürger, Christian, Espeseth, Thomas, Fernández, Guillén, Fisher, Simon E, Flor, Herta, Forstner, Andreas J, Francks, Clyde, Franke, Barbara, Glahn, David C, Gollub, Randy L, Grabe, Hans J, Colodro-Conde, Lucía, Cannon, Dara M, Gruber, Oliver, Håberg, Asta K, Hariri, Ahmad R, Hartman, Catharina A, Hashimoto, Ryota, Heinz, Andreas, Henskens, Frans A, Hillegers, Manon H J, Hoekstra, Pieter J, Holmes, Avram J, Chakravarty, Mallar, Hong, L Elliot, Hopkins, William D, Hulshoff Pol, Hilleke E, Jernigan, Terry L, Jönsson, Erik G, Kahn, René S, Kennedy, Martin A, Kircher, Tilo T J, Kochunov, Peter, Kwok, John B J, Chen, Qiang, Le Hellard, Stephanie, Loughland, Carmel M, Martin, Nicholas G, Martinot, Jean-Luc, McDonald, Colm, McMahon, Katie L, Meyer-Lindenberg, Andreas, Michie, Patricia T, Morey, Rajendra A, Mowry, Bryan, Cheung, Joshua W, Nyberg, Lars, Oosterlaan, Jaap, Ophoff, Roel A, Pantelis, Christos, Paus, Tomas, Pausova, Zdenka, Penninx, Brenda W J H, Polderman, Tinca J C, Posthuma, Danielle, Rietschel, Marcella, Couvy-Duchesne, Baptiste, Roffman, Joshua L, Rowland, Laura M, Sachdev, Perminder S, Sämann, Philipp G, Schall, Ulrich, Schumann, Gunter, Scott, Rodney J, Sim, Kang, Sisodiya, Sanjay M, Smoller, Jordan W, Dale, Anders M, Sommer, Iris E, St Pourcain, Beate, Stein, Dan J, Toga, Arthur W, Trollor, Julian N, Van der Wee, Nic J A, van 't Ent, Dennis, Völzke, Henry, Walter, Henrik, Weber, Bernd, Dalvie, Shareefa, Weinberger, Daniel R, Wright, Margaret J, Zhou, Juan, Stein, Jason L, Thompson, Paul M, Medland, Sarah E, Consortium, Enhancing NeuroImaging Genetics through Meta-Analysis, Witte, A Veronica, Darin, Abigail, Fleisher, Adam, de Araujo, Tânia K, Pierce, Aimee, Mintz, Akiva, Lerner, Alan, Reith, Alastair D, Hofman, Albert, Espay, Alberto, Ihlenfeld, Albrecht, Ing, Alex, Iranzo, Alex, Beiser, Alexa S, de Zubicaray, Greig I, Norbash, Alexander, Barbot, Alexis, Rudolph, Alice, Portillo, Alicia, Chalker, Alison, Levey, Allan I, Rosen, Allyson, Smith, Amanda, Catafau, Ana, de Zwarte, Sonja M C, Ulysse, Anaztasia, Uitterlinden, André G, Becker, Andreas, Budson, Andrew E, Kertesz, Andrew, Siderowf, Andrew, Bralten, Janita, den Braber, Anouk, Singleton, Andrew, James, Angela, Oliver, Angela, Mishra, Aniket, Hake, Ann Marie, Burke, Anna, Sarrael, Antero, Porsteinsson, Anton P, Stringaris, Argyris, McCoy, Arita, Doan, Nhat Trung, Villringer, Arno, Lenahan, Art, Toga, Arthur, Bokde, Arun, Rawlins, Ashlee, Lamb, Ashley, Lee, Athena, Raj, Balebail Ashok, Tran, Baochan, Dohm, Katharina, Ruggeri, Barbara, Saba, Barbara, Lane, Barton, Yanez, Beatriz, Ances, Beau, Dunlop, Becky, Mudge, Benita, Ravina, Bernard, Ittermann, Bernd, Ehrlich, Stefan, van Noort, Betteke, Lind, Betty, Shah, Bina, Stefanovic, Bojana, Goldstein, Bonnie S, Bonakdarpour, Borna, Matthews, Brandy R, Borowski, Bret, Ott, Brian R, Reynolds, Brigid, Engelbrecht, Hannah-Ruth, Mollenhauer, Brit, Miller, Bruce L, Psaty, Bruce M, Spann, Bryan M, Sadowsky, Carl, Linder, Carly, Franz, Carol E, Tanner, Caroline, Kopil, Catherine, Thomas, Cathi-Ann, Erk, Susanne, Ward, Chad, Bernick, Charles, Smith, Charles D, DeCarli, Charles, Caspell, Chelsea, Deeley, Cheryl, Riordan, Cheryl, Mathis, Chet, Onyike, Chiadi, Heyn, Chris Chinthaka, Fan, Chun Chieh, Hosein, Chris, Leach, Christi, Bÿchel, Christian, Gigliotti, Christina, Hunter, Christine, Belden, Christine M, Tzourio, Christophe, Coffey, Christopher, van Dyck, Christopher H, Clark, Christopher M, Fedko, Iryna O, Wu, Chuang-Kuo, Albers, Colleen S, Chu, Congying, Brand, Connie, Isensee, Corinna, van Duijn, Cornelia M, Bishop, Courtney, Bodge, Courtney, Foley, Sonya F, Tatsuoka, Curtis, Casaceli, Cynthia, Carlsson, Cynthia M, Mathews, Dana, D'Agostino, Daniel, Silverman, Daniel H S, Marson, Daniel, Berg, Daniela, Harvey, Danielle, Jennings, Danna, Ford, Judith M, Wolk, David A, Goldstein, David B, Bachman, David, Brooks, David, Clark, David, Geldmacher, David, Hart, David, Holtzman, David, Jones, David, Hibar, Derrek P, Fukunaga, Masaki, Knopman, David, Hewitt, David L, Perry, David, Russell, David, Standaert, David, Winkfield, David, Green, Davis Robert C, Fontaine, Deborah, Miller, Delwyn D, Gessert, Devon, Garrett, Melanie E, Kerwin, Diana, Willeke, Diana, Drost, Dick, Papadopoulos, Dimitri, Rowe, Dominic, Simpson, Donna M, Muni, Donna, Galasko, Douglas, Scharre, Douglas W, Fillmer, Ariane, Ge, Tian, Bartha, Rob, Celmins, Dzintra, Zimmerman, Earl A, Teng, Edmond, Tolosa, Eduardo, Coleman, Edward, Zamrini, Edward, Mitsis, Effie, Finger, Elizabeth, Giddaluru, Sudheer, Oates, Elizabeth, Sosa, Elizabeth, Woo, Ellen, Rogalski, Emily, Lethbridge, Emma, Dooley, Eoin, Foster, Eric, Reiman, Eric M, Quinlan, Erin Burke, Goldman, Aaron L, Franklin, Erin, Heinzen, Erin L, Fletcher, Evan, Sprenger, Fabienne, Crivello, Fabrice, Biondo, Francesca, Parfitt, Francine, Hefti, Franz, Beyer, Frauke, Nees, Frauke, Green, Melissa J, Leonard, Gabriel, Robert, Gabriel, Thai, Gaby, Marshall, Gad A, Barker, Gareth, Conrad, Gary, Tremont, Geoffrey, Bartzokis, George, Groenewold, Nynke A, Hsiung, Ging-Yuek Robin, Malferrari, Giulia, Chiang, Gloria, Pearlson, Godfrey D, Liang, Grace, Jicha, Greg, Sorensen, Greg, Todd, Gretchen, Jimenez, Gustavo, Grotegerd, Dominik, Zare, Habil, Grabe, Hans Jörgen, Vanderswag, Helen, Schmidt, Helena, Venkov, Heli, Lemaitre, Hervé, Gurholt, Tiril P, Grossman, Hillel, Shill, Holly, Soares, Holly, Lin, Honghuang, Capote, Horacio, Bergman, Howard, Chertkow, Howard, Feldman, Howard, Fillit, Howard, Rosen, Howard J, Gutman, Boris A, Koleva, Hristina, Fernandez, Hubert, Garavan, Hugh, Shim, Hyungsub, Grachev, Igor D, Richard, Irene, Filippi, Irina, Rachinsky, Irina, Wurster, Isabel, Lind, Penelope A, Hansell, Narelle K, Mintzer, Jacobo, Ziolkowski, Jaimie, Brewer, James, Lah, James J, Leverenz, James, Becker, James T, Tetrud, James, Singleton-Garvin, Jamika, Egebjerg, Jan, Cellar, Janet S, Harris, Mathew A, Pentilla, Jani, Brosch, Jared R, Tinklenberg, Jared, Karlawish, Jason H, Meyer, Javier Villanueva, Himali, Jayandra J, Poline, Jean-Baptiste, Gunter, Jeff, Kaye, Jeffrey A, Harrison, Marc B, Dalley, Jeffrey, Burns, Jeffrey M, Petrella, Jeffrey R, Mule, Jennifer, Salazar, Jennifer, Rotter, Jerome I, Yesavage, Jerome, Cedarbaum, Jesse, Jiang, Jiyang, Haswell, Courtney C, Allard, Joanne, Lord, Joanne L, Hetelle, Joel, Kwok, John B, Brockington, John, Morris, John C, Hsiao, John, Morris, John, Olichney, John, Trojanowki, John Q, Hauser, Michael, Rogers, John, Seibyl, John, Yankey, Jon, Dubow, Jordan S, Jankovic, Joseph, Quinn, Joseph, Kass, Joseph S, Taylor, Joy L, Heidebrink, Judith L, Herms, Stefan, Trollor, Julian, Fröhner, Juliane, Anderson, Karen, Blank, Karen, Crawford, Karen, Smith, Karen Ekstam, Bell, Karen L, Williams, Karen, Kieburtz, Karl, Heslenfeld, Dirk J, Gauss, Katharina, Gloer, Katherine, Johnson, Kathleen, Tingus, Kathleen, DeMarco, Kathryn, Sink, Kaycee M, Hawkins, Keith A, Johnson, Keith A, Kantarci, Kejal, Ho, New Fei, Faber, Kelley, Harless, Kelly, Makino, Kelly M, Marek, Kenneth, Spicer, Kenneth, Shianna, Kevin, Chen, Kewei, Nam, Ki Won, Martin, Kim, Poki-Walker, Kim, Hoehn, David, Seppi, Klaus, Johnson, Kris, Fargher, Kristin, Lipowski, Kristine, Espay, Kristy, Womack, Kyle, Chahine, Lama, Flashman, Laura A, Daedelow, Laura, Hoffmann, Per, Leary, Laura, Beckett, Laurel, Honig, Lawrence S, Thal, Leon, Shaw, Leslie M, Kuller, Lew, Apostolova, Liana, Teodoro, Liberty, Rees, Linda, Pizzagalli, Fabrizio, Holleran, Laurena, Lewis, Lindsay, Hergesheimer, Lindsey, Silbert, Lisa C, Ravdin, Lisa, Taylor-Reinwald, Lisa, Uribe, Liz, Schneider, Lon S, Daiello, Lori A, Richer, Louis, Poustka, Luise, Hoogman, Martine, Pirpamer, Lukas, Mesulam, M Marcel, Ismail, M Saleem, Ranola, Madelaine, Korecka, Magdalena, Raichle, Marc, Seltzer, Marc, van der Brug, Marcel, Hottenga, Jouke-Jan, Mesulam, Marek-Marsel, Carrillo, Maria, Carroll, Maria, Knol, Maria J, Kataki, Maria, Greig-Custo, Maria T, Paillere, Marie-Laure, Albert, Marilyn, Love, Marissa Natelson, Ikeda, Masashi, Mintun, Mark A, Frasier, Mark, Logue, Mark, Minton, Mark, Loeffler, Markus, Scholz, Markus, Baca, Marne, Farlow, Martin R, Sadowski, Martin, Janowitz, Deborah, Creech, Mary L, Hynes, Mary L, Quiceno, Mary, Oakley, MaryAnn, Harris, Mat, Senjem, Matt, Bernstein, Matthew, Panizzon, Matthew S, Stern, Matthew, Becerra, Mauricio, Jansen, Iris E, Witbracht, Megan, Vernooij, Meike W, Brandabur, Melanie, Keltz, Melanie, Lamar, Melissa, Yang, Mia, Ahlijanian, Michael, Borrie, Michael, Neale, Michael C, Donohue, Michael, Jia, Tianye, Lyons, Michael J, Lin, Michael, Rapp, Michael, Smolka, Michael, Weiner, Michael W, Weiner, Michael, Figurski, Michal, Perron, Michel, Assaly, Michele, Luciano, Michelle, Jockwitz, Christiane, Rainka, Michelle, Dang, Mimi, Sheikh, Mohammed O, Ghanbari, Mohsen, Gaikwad, Mrunalini, Chowdhury, Munir, Trncic, Nadira, Amin, Najaf, Johnson, Nancy, Kanai, Ryota, Kowalksi, Nancy, Monahan, Nancy, Gillespie, Nathan A, Pacini, Nathaniel, Buckholtz, Neil, Kowall, Neil, Graff-Radford, Neill R, Fox, Nick, Pavese, Nicola, Karama, Sherif, Cairns, Nigel J, Schuff, Norbert, Foster, Norm, Relkin, Norman, Oyonumo, Ntekim E, Pomara, Nunzio, James, Olga, Ogunlana, Olu, Ching, Christopher R K, Kasperaviciute, Dalia, Carmichael, Owen, Doraiswamy, P Murali, Casalin, Paola, Barone, Paolo, Fatica, Parianne, Conrod, Patricia, Johnson, Patricia Lynn, Samuels, Patricia, Aisen, Paul, Malloy, Paul, Kaufmann, Tobias, Thompson, Paul, Ogrocki, Paula, Bezivin-Frere, Pauline, Maillard, Pauline, Fontoura, Paulo, Taylor, Peggy, Hogarth, Penelope, Gowland, Penny, Davies, Peter, Kelly, Sinead, Hardy, Peter, Snyder, Peter J, Snyder, Peter, Amouyel, Philippe, Muglia, Pierandrea, Tariot, Pierre, Lu, Po H, Varma, Pradeep, Vemuri, Prashanthi, Kikuchi, Masataka, Doody, Rachelle S, Carter, Raina, Shah, Raj C, Griffith, Randall, Yeh, Randy, Duara, Ranjan, Tarawneh, Rawan, James, Raymond, Turner, Raymond Scott, Klein, Marieke, Hernando, Raymundo, Silverstein, Rebecca, Sperling, Reisa A, Wilson, Renee, Carson, Richard E, Frank, Richard, El Khouli, Riham, Koeppe, Robert A, Santulli, Robert B, Knapp, Michael, Hauser, Robert, Umek, Robert, Radtke, Rodney, Killiany, Ronald, Petersen, Ronald, Rodriguez, Rosemarie, Miranda, Ruben, Knodt, Annchen R, Bruehl, Ruediger, Xia, Rui, Swerdlow, Russell H, Ottmann, Ruth, Millenet, Sabina, Borges-Neto, Salvador, Frank, Samuel, Black, Sandra, Weintraub, Sandra, Obradov, Sanja, Krämer, Bernd, Asthana, Sanjay, Vaishnavi, Sanjeev, Dolen, Sara, Mason, Sara S, Hohmann, Sarah, Kremen, Sarah, Miller, Sarah, Walter, Sarah, Herring, Scott, Neu, Scott, Lam, Max, Aydin, Semiha, Ahmad, Shahzad, Harlan, Sherry, Sirrel, Sherye A, Lasch, Shirley, Hu, Shu-Ching, Li, Shuo, Kittur, Smita, Chowdhury, Sohini, Lancaster, Thomas M, Pawluczyk, Sonia, Maingault, Sophie, Schneider, Stacy, Seiler, Stephan, Guthrie, Stephanie, Kielb, Stephanie, Reeder, Stephanie, Correia, Stephen, Pasternak, Stephen, McMahon, Mary Agnes B, Lee, Phil H, Salloway, Stephen, Johnson, Sterling, Williams, Steve, Chao, Steven, Arnold, Steven E, Paul, Steven, Potkin, Steven, Factor, Stewart, Isaacson, Stuart, Lett, Tristram A, Kim, Sungeun, Ainscough, Susan, Schultz, Susan K, Landau, Susan, Mendick, Susan, Rountree, Susan, Ostrowizki, Suzanne, Veillette, Suzanne, van der Lee, Sven J, Desrivieres, Sylvane, Lewis, Lindsay B, Lee, T-Y, Simuni, Tanya, Foroud, Tatiana, Foroud, Tatiana M, Wong, Terence Z, Villena, Teresa, Comery, Thomas, Obisesan, Thomas O, Lopes-Cendes, Iscia, Banaschewski, Tobias, Sherer, Todd, Montine, Tom, Paus, Tomáš, Robbins, Trevor, Bromberg, Uli, Völker, Uwe, Pavlik, Valory, Arnedo, Vanessa, Kiyasova, Vera, Bates, Vernice, Logovinsky, Veronika, Sossi, Vesna, Shibley, Victoria, Frouin, Vincent, Lee, Virginia, Poewe, Werner, Jagust, William, Brooks, William M, Macciardi, Fabio, Pavlosky, William, Potter, William, Kremen, William S, Longstreth, William T, Niessen, Wiro J, Jian, Xueqiu, Stern, Yaakov, Saba, Yasaman, Cabrera, Yuliana, Grimmer, Yvonne, Marquand, Andre F, Khachaturian, Zaven, Mari, Zoltan, Mathias, Samuel R, Melzer, Tracy R, Milaneschi, Yuri, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Guided Treatment in Optimal Selected Cancer Patients (GUTS), Clinical Cognitive Neuropsychiatry Research Program (CCNP), Movement Disorder (MD), Alzheimer’s Disease Neuroimaging Initiative, CHARGE Consortium, EPIGEN Consortium, IMAGEN Consortium, SYS Consortium, Parkinson’s Progression Markers Initiative, Stochastics, Biological Psychology, APH - Health Behaviors & Chronic Diseases, APH - Mental Health, Science and Society, Cognitive Psychology, IBBA, APH - Personalized Medicine, Complex Trait Genetics, APH - Methodology, Clinical Neuropsychology, Sociology and Social Gerontology, Amsterdam Neuroscience - Complex Trait Genetics, RS: MHeNs - R2 - Mental Health, Psychiatrie & Neuropsychologie, Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA Klinische Genetica (5), Neurology, Psychiatry, Pediatric surgery, Amsterdam Reproduction & Development (AR&D), Human genetics, APH - Digital Health, Psychology, Precision Medicine Institute of Psychiatry, Child and Adolescent Psychiatry / Psychology, Radiology & Nuclear Medicine, Clinical Genetics, Epidemiology, Medical Informatics, Service NEUROSPIN (NEUROSPIN), Université Paris-Saclay-Direction de Recherche Fondamentale (CEA) (DRF (CEA)), Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA), Neurodegeneratives Diseases Institute (IMN-UMR CNRS 5293), Centre National de la Recherche Scientifique (CNRS), General Paediatrics, ARD - Amsterdam Reproduction and Development, Direction de Recherche Fondamentale (CEA) (DRF (CEA)), and Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Commissariat à l'énergie atomique et aux énergies alternatives (CEA)-Université Paris-Saclay
Subjects: 0301 basic medicine, Netherlands Twin Register (NTR), [SDV]Life Sciences [q-bio], LOCI, Genome-wide association study, Brain mapping, 0302 clinical medicine, Cognition, Cortex (anatomy), ComputingMilieux_MISCELLANEOUS, Cerebral Cortex, 0303 health sciences, Brain Mapping, Multidisciplinary, COMMON VARIANTS, Parkinson Disease, Organ Size, Central sulcus, Magnetic Resonance Imaging, medicine.anatomical_structure, Cerebral cortex, Neuroinformatics, EXPRESSION, endocrine system, central sulcus, SURFACE-AREA, Biology, Article, 03 medical and health sciences, SDG 3 - Good Health and Well-being, Genetic variation, medicine, Attention deficit hyperactivity disorder, Humans, General, Gene, METAANALYSIS, 030304 developmental biology, Progenitor, CORTICAL SULCI, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Genetic variants, Genetic Variation, Attention Deficit Disorder with Hyperactivity, Genetic Loci, Genome-Wide Association Study, functional annotation, medicine.disease, Genetic architecture, 030104 developmental biology, Evolutionary biology, OBSERVER-INDEPENDENT CHARACTERIZATION, Multiple comparisons problem, ddc:320, genome-wide association, Neuroscience, 030217 neurology & neurosurgery
Abstract: Enhancing NeuroImaging Genetics through Meta-Analysis Consortium (ENIGMA)—Genetics working group., The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder.
Published: 2020

25. Effect of FHA and Prn on Bordetella pertussis colonization of mice is dependent on vaccine type and anatomical site

Author: Elles Simonetti, Marieke J. Bart, Frits R. Mooi, Marjolein van Gent, Saskia van Selm, Han G. J. van der Heide, Dimitri A. Diavatopoulos, Joshua Gillard, Kees Heuvelman, Kristianne E. Kok, Ronald de Groot, Marien I. de Jonge, Anne Zeddeman, Evi van Schuppen, Fred van Opzeeland, and Marc J. Eleveld
Subjects: Bacterial Diseases, 0301 basic medicine, Bordetella pertussis, Whooping Cough, Bordetella, Physiology, Mutant, Filamentous haemagglutinin adhesin, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Pathology and Laboratory Medicine, Biochemistry, Mice, Medical Conditions, Spectrum Analysis Techniques, 0302 clinical medicine, Immune Physiology, Medicine and Health Sciences, Public and Occupational Health, Virulence Factors, Bordetella, 030212 general & internal medicine, Lung, Vaccines, Immune System Proteins, Multidisciplinary, biology, Vaccination, Flow Cytometry, Antibodies, Bacterial, Vaccination and Immunization, Bacterial Pathogens, Hemagglutinins, Infectious Diseases, Medical Microbiology, Spectrophotometry, Medicine, Cytophotometry, Pathogens, Anatomy, Pertactin, Antibody, Bacterial Outer Membrane Proteins, Research Article, Infectious Disease Control, Science, Immunology, 030106 microbiology, Nose, Diphtheria-Tetanus-acellular Pertussis Vaccines, Research and Analysis Methods, Microbiology, Antibodies, Frameshift mutation, 03 medical and health sciences, Pertussis, Immunity, Animals, Microbial Pathogens, Bacteria, Organisms, Biology and Life Sciences, Proteins, biology.organism_classification, Gene Expression Regulation, Face, biology.protein, Preventive Medicine, Head
Abstract: Contains fulltext : 225116.pdf (Publisher’s version ) (Open Access) Bordetella pertussis vaccine escape mutants that lack expression of the pertussis antigen pertactin (Prn) have emerged in vaccinated populations in the last 10-20 years. Additionally, clinical isolates lacking another acellular pertussis (aP) vaccine component, filamentous hemagglutinin (FHA), have been found sporadically. Here, we show that both whole-cell pertussis (wP) and aP vaccines induced protection in the lungs of mice, but that the wP vaccine was more effective in nasal clearance. Importantly, bacterial populations isolated from the lungs shifted to an FHA-negative phenotype due to frameshift mutations in the fhaB gene. Loss of FHA expression was strongly selected for in Prn-deficient strains in the lungs following aP but not wP vaccination. The combined loss of Prn and FHA led to complete abrogation of bacterial surface binding by aP-induced serum antibodies. This study demonstrates vaccine- and anatomical site-dependent adaptation of B. pertussis and has major implications for the design of improved pertussis vaccines.
Published: 2020

26. Recessive DNAH9 Loss-of-Function Mutations Cause Laterality Defects and Subtle Respiratory Ciliary-Beating Defects

Author: Lena Jelten, Alper Gezdirici, Borut Peterlin, Claudius Werner, Bryan L. Krock, Cansaran Tanidir, Bernd Dworniczak, Niki T. Loges, Aleš Maver, Inga M. Höben, Elizabeth Goldmuntz, Goran Cuturilo, Zeineb Bakey, Miriam Schmidts, Han G. Brunner, Kaman Wu, Matthew A. Deardorff, Elif Yýlmaz Güleç, Diana Frank, Rim Hjeij, Heike Olbrich, Alyssa Ritter, Petra Pennekamp, Johannes Tebbe, Tabea Nöthe-Menchen, Dinu Antony, Heymut Omran, Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, and MUMC+: DA Klinische Genetica (5)
Subjects: 0301 basic medicine, Axoneme, Mucociliary clearance, LEFT-RIGHT ASYMMETRY, primary ciliary dyskinesia, Video microscopy, Biology, situs inversus, DNAH11, 03 medical and health sciences, HETEROTAXY, outer dynein arm, All institutes and research themes of the Radboud University Medical Center, 0302 clinical medicine, Ciliogenesis, Report, Genetics, medicine, Humans, Cilia, DYSKINESIA, OUTER, Genetics (clinical), Primary ciliary dyskinesia, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], IDENTIFICATION, Kartagener Syndrome, Cilium, Dyneins, RANDOMIZATION, Axonemal Dyneins, medicine.disease, PCD, NEPHRONOPHTHISIS, Cell biology, DNAH9, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], 030104 developmental biology, Phenotype, 030228 respiratory system, BODY ASYMMETRY, Mutation, Motile cilium, HEART, Outer dynein arm, COMMON-CAUSE, Ciliary Motility Disorders
Abstract: Dysfunction of motile monocilia, altering the leftward flow at the embryonic node essential for determination of left-right body asymmetry, is a major cause of laterality defects. Laterality defects are also often associated with reduced mucociliary clearance caused by defective multiple motile cilia of the airway and are responsible for destructive airway disease. Outer dynein arms (ODAs) are essential for ciliary beat generation, and human respiratory cilia contain different ODA heavy chains (HCs): the panaxonemally distributed gamma-HC DNAH5, proximally located beta-HC DNAH11 (defining ODA type 1), and the distally localized beta-HC DNAH9 (defining ODA type 2). Here we report loss-of-function mutations in DNAH9 in five independent families causing situs abnormalities associated with subtle respiratory ciliary dysfunction. Consistent with the observed subtle respiratory phenotype, high-speed video microscopy demonstrates distally impaired ciliary bending in DNAH9 mutant respiratory cilia. DNAH9-deficient cilia also lack other ODA components such as DNAH5, DNAI1, and DNAI2 from the distal axonemal compartment, demonstrating an essential role of DNAH9 for distal axonemal assembly of ODAs type 2. Yeast two-hybrid and co-immunoprecipitation analyses indicate interaction of DNAH9 with the ODA components DNAH5 and DNAI2 as well as the ODA-docking complex component CCDC114. We further show that during ciliogenesis of respiratory cilia, first proximally located DNAH11 and then distally located DNAH9 is assembled in the axoneme. We propose that the beta-HC paralogs DNAH9 and DNAH11 achieved specific functional roles for the distinct axonemal compartments during evolution with human DNAH9 function matching that of ancient beta-HCs such as that of the unicellular Chlamydomonas reinhardtii.
Published: 2018

27. Mutations inPDLIM5are rare in dilated cardiomyopathy but are emerging as potential disease modifiers

Author: Kari Casas, Emma L. Robinson, Radek Szklarczyk, Ingrid P.C. Krapels, Gabriel Kringlen, Mohamed W. Mohamed, Kiely N. James, Godelieve R.F. Claes, Shareef Nahas, Jan F. C. Glatz, Els K. Vanhoutte, Michele M. Pasierb, Arthur van den Wijngaard, Stephane Heymans, Job Verdonschot, Han G. Brunner, Mark R. Hazebroek, RS: Carim - H02 Cardiomyopathy, Promovendi CD, Cardiologie, MUMC+: DA KG Lab Centraal Lab (9), MUMC+: DA KG Polikliniek (9), MUMC+: MA Med Staf Artsass Cardiologie (9), Moleculaire Genetica, MUMC+: MA Med Staf Spec Cardiologie (9), MUMC+: DA Klinische Genetica (5), Klinische Genetica, and RS: GROW - R4 - Reproductive and Perinatal Medicine
Subjects: Male, 0301 basic medicine, Muscle Proteins, Genome-wide association study, VARIANTS, 030105 genetics & heredity, medicine.disease_cause, Exon, Loss of Function Mutation, MYOZ2, Connectin, genetics, Genetics (clinical), Genetics & Heredity, Genetics, genetic modifier, Mutation, Microfilament Proteins, LIM Domain Proteins, Middle Aged, Penetrance, Phenotype, Pedigree, SEVERE FORM, LEADS, ENIGMA HOMOLOG, cardiovascular system, Female, Original Article, Life Sciences & Biomedicine, Adult, Cardiomyopathy, Dilated, lcsh:QH426-470, PROTEINS, Biology, 03 medical and health sciences, Exome Sequencing, medicine, Humans, Genetic Testing, GENOME-WIDE ASSOCIATION, Molecular Biology, Gene, Adaptor Proteins, Signal Transducing, Aged, Genes, Modifier, Science & Technology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Myocardium, Original Articles, LDB3, dilated cardiomyopathy, lcsh:Genetics, 030104 developmental biology, sarcomere, Carrier Proteins
Abstract: Background A causal genetic mutation is found in 40% of families with dilated cardiomyopathy (DCM), leaving a large percentage of families genetically unsolved. This prevents adequate counseling and clear recommendations in these families. We aim to identify novel genes or modifiers associated with DCM. Methods We performed computational ranking of human genes based on coexpression with a predefined set of genes known to be associated with DCM, which allowed us to prioritize gene candidates for their likelihood of being involved in DCM. Top candidates will be checked for variants in the available whole‐exome sequencing data of 142 DCM patients. RNA was isolated from cardiac biopsies to investigate gene expression. Results PDLIM5 was classified as the top candidate. An interesting heterozygous variant (189_190delinsGG) was found in a DCM patient with a known pathogenic truncating TTN‐variant. The PDLIM5 loss‐of‐function (LoF) variant affected all cardiac‐specific isoforms of PDLIM5 and no LoF variants were detected in the same region in a control cohort of 26,000 individuals. RNA expression of PDLIM5 and its direct interactors (MYOT, LDB3, and MYOZ2) was increased in cardiac tissue of this patient, indicating a possible compensatory mechanism. The PDLIM5 variant cosegregated with the TTN‐variant and the phenotype, leading to a high disease penetrance in this family. A second patient was an infant with a homozygous 10 kb‐deletion of exon 2 in PDLIM5 resulting in early‐onset cardiac disease, showing the importance of PDLIM5 in cardiac function. Conclusions Heterozygous PDLIM5 variants are rare and therefore will not have a major contribution in DCM. Although they likely play a role in disease development as this gene plays a major role in contracting cardiomyocytes and homozygous variants lead to early‐onset cardiac disease. Other environmental and/or genetic factors are probably necessary to unveil the cardiac phenotype in PDLIM5 mutation carriers., A computational ranking‐based method performed in whole exome sequencing data of dilated cardiomyopathy patient put PDLIM5 forward as novel gene implicated in this cardiac disease.
Published: 2019

28. Toward clinical and molecular understanding of pathogenic variants in the ZBTB18 gene

Author: Grazia M.S. Mancini, Sonja A. de Munnik, Britt-Marie Anderlid, Han G. Brunner, Servi J. C. Stevens, Vyne van der Schoot, Mariet W. Elting, Conny M. A. Ravenswaaij-Arts, Hanka Venselaar, MUMC+: DA KG Polikliniek (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, Klinische Genetica, MUMC+: DA Klinische Genetica (5), MUMC+: DA KG Lab Centraal Lab (9), Clinical Genetics, and Clinical Cognitive Neuropsychiatry Research Program (CCNP)
Subjects: Male, 0301 basic medicine, Microcephaly, INTELLECTUAL DISABILITY, Developmental Disabilities, homology modeling, Corpus Callosum, Missense mutation, Child, Genetics (clinical), Exome sequencing, Genetics, C2H2 Zinc Finger, Brain, Phenotype, Hypotonia, DNA-Binding Proteins, ZBTB18, Child, Preschool, Muscle Hypotonia, Female, Original Article, DEFINES, Chromosome Deletion, medicine.symptom, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Adolescent, PHENOTYPES, Biology, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, RP58, Exome Sequencing, medicine, Humans, 1Q43Q44, corpus callosum anomalies, Molecular Biology, Gene, Genetic Association Studies, Loss function, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Infant, Original Articles, medicine.disease, Repressor Proteins, 030104 developmental biology, DE-NOVO MUTATIONS, Mutation, C2H2zinc finger (ZNF) domain, Agenesis of Corpus Callosum, Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19]
Abstract: BackgroundPatients with pathogenic variants in ZBTB18 present with Intellectual Disability (ID) with frequent co-occurrence of corpus callosum (CC) anomalies, hypotonia, microcephaly, growth problems and variable facial dysmorphologies. These features illustrate a key role for ZBTB18 in brain development.MethodsPatients with a pathogenic variant in ZBTB18 were detected by diagnostic whole exome sequencing (WES) performed in our center. We reviewed the literature and used GeneMatcher to include other cases. YASARA and WHAT IF were used to provide insight into the structural effect of missense variants located in the C2H2 zinc finger domains of the ZBTB18 protein.ResultsWe give a complete overview of pathogenic variants in ZBTB18 detected to date, showing inconsistent presence of clinical features, including CC anomalies. We present four new cases with a de novo pathogenic variant in the ZBTB18 gene, including the fourth case in which a de novo p.Arg464His variant was found.ConclusionHomology modeling of protein structure points to a variable degree of impaired DNA binding caused by missense variants in these domains probably leading to Loss of Function (LoF). Putative partial LoF may present with a less distinctive phenotype than complete LoF, as seen in truncating variants, which presents with an extensive variability in the phenotypic spectrum. Our data do not support a clear genotype to phenotype correlation.
Published: 2018

29. Titin cardiomyopathy leads to altered mitochondrial energetics, increased fibrosis and long-term life-threatening arrhythmias

Author: Marc van Bilsen, Mark R. Hazebroek, Vanessa P. M. van Empel, Kasper W.J. Derks, Hans-Peter Brunner-La Rocca, Christian Knackstedt, Myrurgia Abdul Hamid, Joergen Bierau, Jort J. Merken, Arantxa Barandiarán Aizpurua, Han G. Brunner, Simon Schalla, Stephane Heymans, Ingrid P.C. Krapels, Ping Wang, Arthur van den Wijngaard, Job A J Verdonschot, Cardiologie, Promovendi CD, RS: CARIM - R2.02 - Cardiomyopathy, Genetica & Celbiologie, MUMC+: DA KG Lab Centraal Lab (9), RS: CARIM - R3.11 - Imaging, MUMC+: MA Med Staf Spec Cardiologie (9), MUMC+: DA Pat Pathologie (9), RS: GROW - R2 - Basic and Translational Cancer Biology, Fysiologie, RS: GROW - R4 - Reproductive and Perinatal Medicine, Klinische Genetica, MUMC+: DA Klinische Genetica (5), and MUMC+: DA KG Polikliniek (9)
Subjects: Cardiac function curve, Systemic disease, medicine.medical_specialty, Cardiomyopathy, Titin, Genotype-phenotype, VARIANTS, 030204 cardiovascular system & hematology, DIAGNOSIS, Muscle hypertrophy, 03 medical and health sciences, RELEVANCE, 0302 clinical medicine, Internal medicine, Genetics, medicine, Humans, Connectin, cardiovascular diseases, 030212 general & internal medicine, POSITION STATEMENT, Cardiac imaging, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], biology, MUTATIONS, business.industry, MORTALITY, Arrhythmias, Cardiac, Dilated cardiomyopathy, Prognosis, DILATED CARDIOMYOPATHY, medicine.disease, Fibrosis, Mitochondria, Mitochondrial, PERICARDIAL DISEASES, Heart failure, ESC WORKING GROUP, cardiovascular system, biology.protein, Cardiology, HEART-FAILURE, Cardiomyopathies, Cardiology and Cardiovascular Medicine, business
Abstract: Contains fulltext : 190758.pdf (Publisher’s version ) (Open Access) Aims: Truncating titin variants (TTNtv) are the most prevalent genetic cause of dilated cardiomyopathy (DCM). We aim to study clinical parameters and long-term outcomes related to the TTNtv genotype and determine the related molecular changes at tissue level in TTNtv DCM patients. Methods and results: A total of 303 consecutive and extensively phenotyped DCM patients (including cardiac imaging, Holter monitoring, and endomyocardial biopsy) underwent DNA sequencing of 47 cardiomyopathy-associated genes including TTN, yielding 38 TTNtv positive (13%) patients. At long-term follow-up (median of 45 months, up to 12 years), TTNtv DCM patients had increased ventricular arrhythmias compared to other DCM, but a similar survival. Arrhythmias are especially prominent in TTNtv patients with an additional environmental trigger (i.e. virus infection, cardiac inflammation, systemic disease, toxic exposure). Importantly, cardiac mass is reduced in TTNtv patients, despite similar cardiac function and dimensions at cardiac magnetic resonance. These enhanced life-threatening arrhythmias and decreased cardiac mass in TTNtv DCM patients go along with significant cardiac energetic and matrix alterations. All components of the mitochondrial electron transport chain are significantly upregulated in TTNtv hearts at RNA-sequencing. Also, interstitial fibrosis was augmented in TTNtv patients at histological and transcript level. Conclusion: Truncating titin variants lead to pronounced cardiac alterations in mitochondrial function, with increased interstitial fibrosis and reduced hypertrophy. Those structural and metabolic alterations in TTNtv hearts go along with increased ventricular arrhythmias at long-term follow-up, with a similar survival and overall cardiac function.
Published: 2018

30. A genotype-first approach identifies an intellectual disability-overweight syndrome caused by PHIP haploinsufficiency

Author: Rolph Pfundt, Bregje W.M. van Bon, Petra de Vries, Carl Baker, Marloes Steehouwer, Bradley P. Coe, Tjitske Kleefstra, Lisenka E.L.M. Vissers, Han G. Brunner, David A. Koolen, Caroline Nava, Daniëlle G. M. Bosch, Anna Hackett, Hilde Van Esch, Fleur Vansenne, Alexander Hoischen, Christian Gilissen, Kali Witherspoon, Heather C Mefford, Martin Jakob Larsen, Janneke H M Schuurs-Hoeijmakers, Malin Kvarnung, Gemma L. Carvill, Bert B.A. de Vries, Fiona Haslam McKenzie, Maartje van de Vorst, Mirella Vinci, Jozef Gecz, Carlo Marcelis, Sandra Jansen, Marijke Bauters, Raphael Bernier, Joris A. Veltman, Corrado Romano, Evan E. Eichler, Ulla A Andersen, Hedi L Claahsen-van der Grinten, Connie T.R.M. Stumpel, Lucia Grillo, Marie Lorraine Monin, Servi J. C. Stevens, MUMC+: DA KG Lab Centraal Lab (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, Klinische Genetica, MUMC+: DA KG Polikliniek (9), and MUMC+: DA Klinische Genetica (5)
Subjects: Male, 0301 basic medicine, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], AUTISM SPECTRUM DISORDERS, Haploinsufficiency, Disease, DOMAIN-INTERACTING PROTEIN, 0302 clinical medicine, Intellectual disability, Genotype, OF-FUNCTION MUTATIONS, SCHIZOPHRENIA, Child, Genetics (clinical), Genetics, DEVELOPMENTAL DELAY, Genotype-first approach, Intracellular Signaling Peptides and Proteins, Vascular damage Radboud Institute for Molecular Life Sciences [Radboudumc 16], Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Syndrome, Phenotype, Sequence Analysis, DNA/methods, Female, Sequence Analysis, Genetic Testing/methods, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Adult, GENES, Adolescent, Biology, Article, SIGNALING PATHWAYS, UBIQUITIN LIGASE, 03 medical and health sciences, All institutes and research themes of the Radboud University Medical Center, Intellectual Disability, medicine, Humans, Genetic Testing, Overweight/genetics, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Reproducibility of Results, LINKED MENTAL-RETARDATION, DNA, Sequence Analysis, DNA, Overweight, medicine.disease, Intellectual Disability/genetics, Human genetics, 030104 developmental biology, DE-NOVO MUTATIONS, Autism, Intracellular Signaling Peptides and Proteins/genetics, 030217 neurology & neurosurgery
Abstract: Genotype-first combined with reverse phenotyping has shown to be a powerful tool in human genetics, especially in the era of next generation sequencing. This combines the identification of individuals with mutations in the same gene and linking these to consistent (endo)phenotypes to establish disease causality. We have performed a MIP (molecular inversion probe)-based targeted re-sequencing study in 3,275 individuals with intellectual disability (ID) to facilitate a genotype-first approach for 24 genes previously implicated in ID.Combining our data with data from a publicly available database, we confirmed 11 of these 24 genes to be relevant for ID. Amongst these, PHIP was shown to have an enrichment of disruptive mutations in the individuals with ID (5 out of 3,275). Through international collaboration, we identified a total of 23 individuals with PHIP mutations and elucidated the associated phenotype. Remarkably, all 23 individuals had developmental delay/ID and the majority were overweight or obese. Other features comprised behavioral problems (hyperactivity, aggression, features of autism and/or mood disorder) and dysmorphisms (full eyebrows and/or synophrys, upturned nose, large ears and tapering fingers). Interestingly, PHIP encodes two protein-isoforms, PHIP/DCAF14 and NDRP, each involved in neurodevelopmental processes, including E3 ubiquitination and neuronal differentiation. Detailed genotype-phenotype analysis points towards haploinsufficiency of PHIP/DCAF14, and not NDRP, as the underlying cause of the phenotype.Thus, we demonstrated the use of large scale re-sequencing by MIPs, followed by reverse phenotyping, as a constructive approach to verify candidate disease genes and identify novel syndromes, highlighted by PHIP haploinsufficiency causing an ID-overweight syndrome. ispartof: European Journal of Human Genetics vol:26 issue:1 pages:54-63 ispartof: location:England status: published
Published: 2018

31. De Novo Missense Mutations in DHX30 Impair Global Translation and Cause a Neurodevelopmental Disorder

Author: Naomi Meeks, Stefan Kindler, Anya Revah-Politi, Alexander P.A. Stegmann, Vinodh Narayanan, Dominique Bonneau, Claudia Schob, Jill A. Rosenfeld, Jennifer E. Posey, Tim M. Strom, LaDonna Immken, Tjitske Kleefstra, Jolanda H. Schieving, Katherine L. Helbig, Estelle Colin, Magalie Barth, Tamar Harel, Matthew J. Huentelman, James R. Lupski, Benjamin Cogné, Han G. Brunner, Yaping Yang, Sébastien Küry, Jenny Morton, Erica H. Gerkes, Keri Ramsey, Marine Tessarech, Zeynep Coban-Akdemir, Shimon Edvardson, Hans-Jürgen Kreienkamp, Nelly Oundjian, Davor Lessel, Christian Kubisch, Thomas Besnard, Jonas Denecke, Orly Elpeleg, Ana M. Claasen, Kelsey Zegar, Mohammad K. Eldomery, Sandra Mercier, Margot R.F. Reijnders, Stéphane Bézieau, Univ Angers, Okina, MUMC+: DA KG Lab Centraal Lab (9), Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA Klinische Genetica (5), Physiopathologie Cardiovasculaire et Mitochondriale (MITOVASC), and Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)
Subjects: 0301 basic medicine, Central Nervous System, Male, DISRUPTION, INTELLECTUAL DISABILITY, Developmental Disabilities, PROTEIN, DISEASE, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual disability, Missense mutation, Global developmental delay, Amino Acids, Child, Genetics (clinical), Genetics, Adenosine Triphosphatases, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Translation (biology), Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], 3. Good health, FAMILY, Child, Preschool, Female, RNA Helicases, MODULE, Adolescent, Mutation, Missense, RNA GRANULES, Biology, Article, Cell Line, 03 medical and health sciences, Stress granule, Cell Line, Tumor, medicine, Humans, HELICASE, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], STRESS GRANULES, Helicase, RNA, Correction, medicine.disease, GENE, 030104 developmental biology, HEK293 Cells, biology.protein, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract: Contains fulltext : 182457.pdf (Publisher’s version ) (Open Access) DHX30 is a member of the family of DExH-box helicases, which use ATP hydrolysis to unwind RNA secondary structures. Here we identified six different de novo missense mutations in DHX30 in twelve unrelated individuals affected by global developmental delay (GDD), intellectual disability (ID), severe speech impairment and gait abnormalities. While four mutations are recurrent, two are unique with one affecting the codon of one recurrent mutation. All amino acid changes are located within highly conserved helicase motifs and were found to either impair ATPase activity or RNA recognition in different in vitro assays. Moreover, protein variants exhibit an increased propensity to trigger stress granule (SG) formation resulting in global translation inhibition. Thus, our findings highlight the prominent role of translation control in development and function of the central nervous system and also provide molecular insight into how DHX30 dysfunction might cause a neurodevelopmental disorder.
Published: 2017

32. Propionic acidemia as a cause of adult-onset dilated cardiomyopathy

Author: Gajja S. Salomons, Arthur van den Wijngaard, Jan F. C. Glatz, Ingrid P.C. Krapels, Jörgen Bierau, Appolonia T J M Helderman-van den Enden, Mark R. Hazebroek, Liesbeth van der Ploeg, Sacha Ferdinandusse, Stephane Heymans, Moniek Riemersma, Han G. Brunner, Martijn C. G. J. Brouwers, AGEM - Amsterdam Gastroenterology Endocrinology Metabolism, Laboratory Genetic Metabolic Diseases, Klinische Genetica, Promovendi CD, RS: CARIM - R2.02 - Cardiomyopathy, MUMC+: DA KG Polikliniek (9), Interne Geneeskunde, MUMC+: MA Endocrinologie (9), RS: CARIM - R3.01 - Vascular complications of diabetes and the metabolic syndrome, MUMC+: TPZ Dietetiek (9), Cardiologie, MUMC+: MA Med Staf Spec Cardiologie (9), Moleculaire Genetica, RS: CARIM - R2.06 - Intermediate cardiac metabolism, MUMC+: DA KG Lab Centraal Lab (9), MUMC+: DA Klinische Genetica (5), AGEM - Inborn errors of metabolism, AGEM - Endocrinology, metabolism and nutrition, Amsterdam Neuroscience - Cellular & Molecular Mechanisms, Laboratory Medicine, and Amsterdam Reproduction & Development (AR&D)
Subjects: 0301 basic medicine, Male, Methylmalonyl-CoA Decarboxylase, Propionic Acidemia, Cardiomyopathy, 030204 cardiovascular system & hematology, Bioinformatics, Compound heterozygosity, GUIDELINES, 0302 clinical medicine, Propionic acidemia, MUTATION, Genetics (clinical), Exome sequencing, Cells, Cultured, COMMITTEE, CARDIOLOGY, Genetics, Aged, 80 and over, Metabolic disorder, Dilated cardiomyopathy, Middle Aged, musculoskeletal system, Pedigree, cardiovascular system, Female, Adult, Cardiomyopathy, Dilated, Heterozygote, Context (language use), Biology, DIAGNOSIS, FREQUENCY, complex mixtures, Article, CLASSIFICATION, 03 medical and health sciences, medicine, Humans, Multiplex ligation-dependent probe amplification, cardiovascular diseases, Aged, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], GENE-THERAPY, Fibroblasts, medicine.disease, DYSFUNCTION, 030104 developmental biology, TASK-FORCE
Abstract: Contains fulltext : 182645.pdf (Publisher’s version ) (Open Access) Dilated cardiomyopathy (DCM) is extremely heterogeneous with a large proportion due to dominantly inherited disease-causing variants in sarcomeric genes. Recessive metabolic diseases may cause DCM, usually with onset in childhood, and in the context of systemic disease. Whether metabolic defects can also cause adult-onset DCM is currently unknown. Therefore, we performed an extensive metabolic screening in 36 consecutive adult-onset DCM patients. Diagnoses were confirmed by Sanger sequencing and multiplex ligation-dependent probe amplification (MLPA). Measurement of propionyl-CoA carboxylase (PCC) activity was done in fibroblasts. Whole exome sequencing (WES) data of 157 additional DCM patients were analyzed for genetic defects. We found a metabolic profile characteristic for propionic acidemia in a patient with severe DCM from 55 years of age. Genetic analysis demonstrated compound heterozygous variants in PCCA. Enzymatic activity of PCC in fibroblasts was markedly reduced. A targeted analysis of the PCCA and PCCB genes using available WES data from 157 further DCM patients subsequently identified another patient with propionic acidemia. This patient had compound heterozygous variants in PCCB, and developed severe DCM from 42 years of age. Adult-onset DCM can be caused by propionic acidemia, an autosomal recessive inheritable metabolic disorder usually presenting as neonatal or childhood disease. Current guidelines advise a low-protein diet to ameliorate or prevent detrimental aspects of the disease. Long-term follow-up of a larger group of patients may show whether this diet would also ameliorate DCM. Our results suggest that diagnostic metabolic screening to identify propionic acidemia and related disorders in DCM patients is justified.
Published: 2017

33. Duplicated Enhancer Region Increases Expression of CTSB and Segregates with Keratolytic Winter Erythema in South African and Norwegian Families

Author: Martin Oti, Bjørn Ivar Haukanes, Thandiswa Ngcungcu, Stine Buechmann-Moller, Tomasz Stokowy, Wayne Grayson, Olav Sundnes, Edward J. Oakeley, Fan Yang, Ivonne M.J.J. van Vlijmen-Willems, Han G. Brunner, Michèle Ramsay, Hans van Bokhoven, Robert Bruccoleri, Jiang Zhu, Thomas Morgan, Kari Merete Ersland, Bolan Linghu, Charlotte von der Lippe, Huiqing Zhou, Torunn Fiskerstrand, Frank Staedtler, Marc Sultan, Joost Schalkwijk, Jan Cezary Sitek, Vidar M. Steen, Joseph D. Szustakowski, Peter R. Hull, Nanguneri Nirmala, Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, and MUMC+: DA Klinische Genetica (5)
Subjects: 0301 basic medicine, Epigenomics, Male, Cathepsin B, DNA Glycosylases, 030207 dermatology & venereal diseases, South Africa, 0302 clinical medicine, Gene Duplication, Gene expression, Gene duplication, DNA-(Apurinic or Apyrimidinic Site) Lyase, Genetics (clinical), Genetics, Regulation of gene expression, integumentary system, Norway, ENCODING CYSTATIN-A, Autosomal dominant trait, Chromosome Mapping, Skin Diseases, Genetic, Pedigree, GENOME, Reconstructive and regenerative medicine Radboud Institute for Molecular Life Sciences [Radboudumc 10], Enhancer Elements, Genetic, MCF-7 Cells, Female, Molecular Developmental Biology, Inflammatory diseases Radboud Institute for Molecular Life Sciences [Radboudumc 5], Chromosomes, Human, Pair 8, Genetic Markers, DNA Copy Number Variations, DNA-SEQUENCING DATA, Biology, 03 medical and health sciences, EPIDERMAL DIFFERENTIATION, medicine, Humans, Enhancer, Gene, OUDTSHOORN SKIN, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], KERATINOCYTES, Keratosis, medicine.disease, Molecular biology, GENE, 030104 developmental biology, Gene Expression Regulation, CHROMOSOME 8P22-P23, Erythema, CATHEPSIN-L, ERYTHROKERATOLYSIS-HIEMALIS, Case-Control Studies, Keratolytic winter erythema, Epidermis
Abstract: Contains fulltext : 174194.pdf (Publisher’s version ) (Open Access) Keratolytic winter erythema (KWE) is a rare autosomal-dominant skin disorder characterized by recurrent episodes of palmoplantar erythema and epidermal peeling. KWE was previously mapped to 8p23.1-p22 (KWE critical region) in South African families. Using targeted resequencing of the KWE critical region in five South African families and SNP array and whole-genome sequencing in two Norwegian families, we identified two overlapping tandem duplications of 7.67 kb (South Africans) and 15.93 kb (Norwegians). The duplications segregated with the disease and were located upstream of CTSB, a gene encoding cathepsin B, a cysteine protease involved in keratinocyte homeostasis. Included in the 2.62 kb overlapping region of these duplications is an enhancer element that is active in epidermal keratinocytes. The activity of this enhancer correlated with CTSB expression in normal differentiating keratinocytes and other cell lines, but not with FDFT1 or NEIL2 expression. Gene expression (qPCR) analysis and immunohistochemistry of the palmar epidermis demonstrated significantly increased expression of CTSB, as well as stronger staining of cathepsin B in the stratum granulosum of affected individuals than in that of control individuals. Analysis of higher-order chromatin structure data and RNA polymerase II ChIA-PET data from MCF-7 cells did not suggest remote effects of the enhancer. In conclusion, KWE in South African and Norwegian families is caused by tandem duplications in a non-coding genomic region containing an active enhancer element for CTSB, resulting in upregulation of this gene in affected individuals.
Published: 2017

34. Quantification of Phenotype Information Aids the Identification of Novel Disease Genes

Author: Bregje W.M. van Bon, Christian Gilissen, Han G. Brunner, David A. Koolen, Bert B.A. de Vries, Arjan P.M. de Brouwer, Jelle J. Goeman, Claudia J.M. van Amen-Hellebrekers, Sandra Jansen, Anneke T. Vulto-van Silfhout, Erik A. Sistermans, MUMC+: DA Klinische Genetica (5), Klinische Genetica, RS: FHML non-thematic output, Amsterdam Reproduction & Development (AR&D), Human genetics, and Amsterdam Neuroscience - Complex Trait Genetics
Subjects: 0301 basic medicine, Mutation rate, INTELLECTUAL DISABILITY, Genotype, Cancer development and immune defence Radboud Institute for Molecular Life Sciences [Radboudumc 2], systematic phenotyping, AUTISM SPECTRUM DISORDERS, de novo mutations, Disease, 030105 genetics & heredity, Biology, 03 medical and health sciences, Intellectual disability, Genetics, medicine, Humans, statistical approach, Genetic Predisposition to Disease, phenotype features, Gene, Genetics (clinical), Genetic Association Studies, patient cohorts, Disease gene, Models, Statistical, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Models, Genetic, DEVELOPMENTAL DELAY, Reproducibility of Results, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], medicine.disease, Phenotype, 3. Good health, ONTOLOGY, 030104 developmental biology, DE-NOVO MUTATIONS, DISCOVERY, Cohort, IMPLICATE, Identification (biology), Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]
Abstract: Contains fulltext : 174800.pdf (Publisher’s version ) (Open Access) Next-generation sequencing led to the identification of many potential novel disease genes. The presence of mutations in the same gene in multiple unrelated patients is, however, a priori insufficient to establish that these genes are truly involved in the respective disease. Here, we show how phenotype information can be incorporated within statistical approaches to provide additional evidence for the causality of mutations. We developed a broadly applicable statistical model that integrates gene-specific mutation rates, cohort size, mutation type, and phenotype frequency information to assess the chance of identifying de novo mutations affecting the same gene in multiple patients with shared phenotype features. We demonstrate our approach based on the frequency of phenotype features present in a unique cohort of 6,149 patients with intellectual disability. We show that our combined approach can decrease the number of patients required to identify novel disease genes, especially for patients with combinations of rare phenotypes. In conclusion, we show how integrating genotype-phenotype information can aid significantly in the interpretation of de novo mutations in potential novel disease genes.
Published: 2017

35. YY1 Haploinsufficiency Causes an Intellectual Disability Syndrome Featuring Transcriptional and Chromatin Dysfunction

Author: Asbjørg Stray-Pedersen, Anne Ronan, Yunru Shao, Eric Haan, Katharina Steindl, Zöe Powis, Perla Thulin, Giuseppe Testa, Janneke H M Schuurs-Hoeijmakers, William J. Craigen, Raman Kumar, David Rodriguez-Buritica, Michele Gabriele, Laura S. Farach, Susanne Kjaergaard, Rolph Pfundt, Jillian Nicholl, Jozef Gecz, Petter Strømme, Stefan H. Lelieveld, Kenjiro Kosaki, Sally Ann Lynch, Kimberly M. Nugent, Willy M. Nillesen, Bregje W.M. van Bon, Jill A. Rosenfeld, Charlotte Brasch-Andersen, Eirik Frengen, Lisenka E.L.M. Vissers, Scott D. McLean, Evelyn Douglas, Joris Andrieux, David A. Koolen, Anneke T. Vulto-van Silfhout, Han G. Brunner, Arie van Haeringen, Jenny Morton, Sophie Patrier, Anita Rauch, Christeen Ramane J. Pedurupillay, Pierre-Luc Germain, Peter J. Anderson, Christian Gilissen, Christian P. Schaaf, Alessandro Vitriolo, Jennifer Friedman, Toshiki Takenouchi, Pascal Chambon, Bert B.A. de Vries, Doriana Misceo, Pernille Mathiesen Tørring, Family Medicine, MUMC+: DA Klinische Genetica (5), Klinische Genetica, and RS: FHML non-thematic output
Subjects: Male, Models, Molecular, 0301 basic medicine, Transcription, Genetic, Haploinsufficiency, Cohort Studies, Histones, 0302 clinical medicine, Missense mutation, Lymphocytes, YY1 Transcription Factor, Genetics (clinical), GENE-EXPRESSION, Genetics, KANSL1 CAUSE, Acetylation, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], DEMETHYLASE JMJD3, Chromatin, Enhancer Elements, Genetic, Child, Preschool, embryonic structures, Female, Neurodevelopmental disorders Radboud Institute for Molecular Life Sciences [Radboudumc 7], STEM-CELLS, Protein Binding, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Chromatin Immunoprecipitation, LIQUID WATER, Adolescent, Mutation, Missense, Repressor, Biology, Methylation, Article, 17Q21.31 MICRODELETION SYNDROME, 03 medical and health sciences, ADENOVIRUS E1A, Protein Domains, Intellectual Disability, Journal Article, Humans, Enhancer, Transcription factor, Hemizygote, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Base Sequence, POTENTIAL FUNCTIONS, Activator (genetics), YY1, MUTATIONS, Gene Ontology, 030104 developmental biology, Haplotypes, 030217 neurology & neurosurgery, MENTAL-RETARDATION
Abstract: Contains fulltext : 174704.pdf (Publisher’s version ) (Open Access) Yin and yang 1 (YY1) is a well-known zinc-finger transcription factor with crucial roles in normal development and malignancy. YY1 acts both as a repressor and as an activator of gene expression. We have identified 23 individuals with de novo mutations or deletions of YY1 and phenotypic features that define a syndrome of cognitive impairment, behavioral alterations, intrauterine growth restriction, feeding problems, and various congenital malformations. Our combined clinical and molecular data define "YY1 syndrome" as a haploinsufficiency syndrome. Through immunoprecipitation of YY1-bound chromatin from affected individuals' cells with antibodies recognizing both ends of the protein, we show that YY1 deletions and missense mutations lead to a global loss of YY1 binding with a preferential retention at high-occupancy sites. Finally, we uncover a widespread loss of H3K27 acetylation in particular on the YY1-bound enhancers, underscoring a crucial role for YY1 in enhancer regulation. Collectively, these results define a clinical syndrome caused by haploinsufficiency of YY1 through dysregulation of key transcriptional regulators.
Published: 2017

36. Rare novel variants in the ZIC3 gene cause X-linked heterotaxy

Author: Iben Bache, Arthur van den Wijngaard, Crool Velter, Ingrid P.C. Krapels, Kristiina Avela, Sonja Chocron, Florence H J van Tienen, Bálint Nagy, Godelieve R.F. Claes, Aimee D C Paulussen, Lisa Leth Maroun, Irene Valenzuela, Anja Steyls, Jeroen Bakkers, Jo Vanoevelen, Hubert J.M. Smeets, Catarina Lundin, Han G. Brunner, Gita M. B. Tan-Sindhunata, Human genetics, Hubrecht Institute for Developmental Biology and Stem Cell Research, Genetica & Celbiologie, RS: CARIM School for Cardiovascular Diseases, RS: CARIM - R2.10 - Mitochondrial disease, MUMC+: DA KG Lab Centraal Lab (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Polikliniek (9), MUMC+: DA Klinische Genetica (5), and Klinische Genetica
Subjects: Male, 0301 basic medicine, medicine.medical_specialty, ved/biology.organism_classification_rank.species, Mutation, Missense, Dextrocardia, Heterotaxy Syndrome, 030105 genetics & heredity, Biology, Klinikai orvostudományok, medicine.disease_cause, Bioinformatics, Article, 03 medical and health sciences, Fetus, Pregnancy, Genetic linkage, Molecular genetics, Journal Article, Genetics, medicine, Animals, Humans, Missense mutation, Genetics(clinical), Model organism, Gene, Zebrafish, Genetics (clinical), Homeodomain Proteins, Mutation, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], ved/biology, Infant, Newborn, Genetic Diseases, X-Linked, Orvostudományok, Human genetics, 3. Good health, Protein Transport, 030104 developmental biology, Female, Heterotaxy, Gene Deletion, HeLa Cells, Transcription Factors
Abstract: Contains fulltext : 168089.pdf (Publisher’s version ) (Open Access) Variants in the ZIC3 gene are rare, but have demonstrated their profound clinical significance in X-linked heterotaxy, affecting in particular male patients with abnormal arrangement of thoracic and visceral organs. Several reports have shown relevance of ZIC3 gene variants in both familial and sporadic cases and with a predominance of mutations detected in zinc-finger domains. No studies so far have assessed the functional consequences of ZIC3 variants in an in vivo model organism. A study population of 348 patients collected over more than 10 years with a large variety of congenital heart disease including heterotaxy was screened for variants in the ZIC3 gene. Functional effects of three variants were assessed both in vitro and in vivo in the zebrafish. We identified six novel pathogenic variants (1,7%), all in either male patients with heterotaxy (n=5) or a female patient with multiple male deaths due to heterotaxy in the family (n=1). All variants were located within the zinc-finger domains or leading to a truncation before these domains. Truncating variants showed abnormal trafficking of mutated ZIC3 proteins, whereas the missense variant showed normal trafficking. Overexpression of wild-type and mutated ZIC protein in zebrafish showed full non-functionality of the two frame-shift variants and partial activity of the missense variant compared with wild-type, further underscoring the pathogenic character of these variants. Concluding, we greatly expanded the number of causative variants in ZIC3 and delineated the functional effects of three variants using in vitro and in vivo model systems.
Published: 2016

37. Integrating healthcare and research genetic data empowers the discovery of 28 novel developmental disorders

Author: Matthew E. Hurles, Deciphering Developmental Disorders Study, de Boer E, Jeffrey C. Barrett, Kevin J. Arvai, Stefan H. Lelieveld, Giuseppe Gallone, Patrick J. Short, Helen V. Firth, Hilary C. Martin, Christian Gilissen, Alison Yeung, Joanna Kaplanis, Petr Danecek, Ni Huang, Rebecca I. Torene, Kaitlin E. Samocha, R. Pfundt, Helger G. Yntema, Han G. Brunner, Caroline F. Wright, Ruth Y. Eberhardt, Jane Juusola, Reijnders Mrf., Inigo Martincorena, David R. FitzPatrick, Jeremy F. McRae, Eugene J. Gardner, Vissers Lelm, Zhancheng Zhang, Kyle Retterer, Jenny Lord, and Laurens Wiel
Subjects: 0303 health sciences, Genetic data, Computational biology, Biology, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, chemistry, Penetrant (biochemical), Exome, Gene, 030217 neurology & neurosurgery, De novo mutations, 030304 developmental biology
Abstract: SummaryDe novo mutations (DNMs) in protein-coding genes are a well-established cause of developmental disorders (DD). However, known DD-associated genes only account for a minority of the observed excess of such DNMs. To identify novel DD-associated genes, we integrated healthcare and research exome sequences on 31,058 DD parent-offspring trios, and developed a simulation-based statistical test to identify gene-specific enrichments of DNMs. We identified 285 significantly DD-associated genes, including 28 not previously robustly associated with DDs. Despite detecting more DD-associated genes than in any previous study, much of the excess of DNMs of protein-coding genes remains unaccounted for. Modelling suggests that over 1,000 novel DD-associated genes await discovery, many of which are likely to be less penetrant than the currently known genes. Research access to clinical diagnostic datasets will be critical for completing the map of dominant DDs.
Published: 2019

38. Brunner Syndrome associated MAOA dysfunction in human induced dopaminergic neurons results in dysregulated NMDAR expression and increased network activity

Author: Dirk Schubert, Barbara Franke, Sarah Kittel-Schneider, Maren Bormann, Marina Hakobjan, J.R. van Rhijn, Britt Mossink, Yingjie Shi, Nael Nadif Kasri, Han G. Brunner, and Monica Frega
Subjects: biology, Brunner syndrome, Dopaminergic, Neurotransmission, Serotonergic, medicine.disease, Monoamine neurotransmitter, Dopamine, biology.protein, medicine, Serotonin, Monoamine oxidase A, Neuroscience, medicine.drug
Abstract: Monoamine oxidase A (MAOA) is an enzyme that catalyzes the degradation of dopamine, noradrenaline, and serotonin. Regulation of monoamine neurotransmitter abundance through MAOA activity strongly affects motor control, emotion, and cognitive function. Mutations in MAOA cause Brunner Syndrome, which is characterized by impulsive aggressive behavior and mild intellectual disability (ID). The impaired MAOA activity in Brunner Syndrome patients results in bioamine aberration, but it is currently unknown how this affects neuronal function. MAOA is highly expressed in serotonergic and dopaminergic neurons, and dysfunction of both neurotransmission systems is associated with aggressive behavior in mice and humans. Research has so far mainly focused on the serotonergic system. Here, we generated human induced pluripotent stem cell-derived induced dopaminergic neurons (iDANs) from individuals with known MAOA mutations, to investigate MAOA-dependent effects on dopamine neuronal function in the context of Brunner Syndrome. We assessed iDAN lines from three patients and combined data from morphological analysis, gene expression, single-cell electrophysiology, and network analysis using micro-electrode arrays (MEAs). We observed mutation-dependent functional effects as well as overlapping changes in iDAN morphology. The most striking effect was a clear increase in N-methyl-D-aspartate (NMDA) receptor mRNA expression in all patient lines. A marked increase was also seen in coordinated network activity (network bursts) on the MEA in all patient lines, while single-cell intrinsic properties and spontaneous excitatory postsynaptic currents activity appeared normal. Together, our data indicate that dysfunction of MAOA leads to increased coordinated network activity in iDANs, possibly caused by increased synaptic NMDA receptor expression.
Published: 2019
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39. The importance of a multifactorial approach for (inter)national surveillance of Shigella spp. and entero-invasive Escherichia coli

Author: Roan Pijnacker, Sjoerd Kuiling, Ramón C.E.A. Noomen, Evy M. Heerkens, Han G. J. van der Heide, Frans A. G. Reubsaet, Airien Harpal, B. J. A. (Dieneke) Hoeve-Bakker, John W. A. Rossen, Maaike J. C. van den Beld, Amber C A Hendriks, A.M.D. Kooistra-Smid, and Dyogo Borst
Subjects: medicine, Shigella, INVASIVE ESCHERICHIA COLI, Biology, medicine.disease_cause, Microbiology
Abstract: Background: Shigella spp. and entero-invasive Escherichia coli (EIEC) can cause mild diarrhea to dysentery. In the Netherlands, although shigellosis is a notifiable disease, there is no laboratory surveillance for Shigella spp. and EIEC in place. Consequently, the population structure for circulating Shigella spp. and EIEC isolates is not known. This study describes the phenotypic and serological characteristics, the phenotypic and genetic antimicrobial resistance profiles, the virulence gene profiles, the classic multi-locus sequence types (MSLT) and core genome MLST (cgMLST) types, and the epidemiology of Shigella spp. and EIEC isolates collected during a cross-sectional study in the Netherlands in 2016 and 2017. Results: S. sonnei, S. flexneri and EIEC were predominantly detected in the Netherlands. A substantial part of the characterized isolates was resistant to antimicrobials advised for treatment, i.e., 73% was phenotypically resistant to co-trimoxazol and 19% to ciprofloxacin. Antimicrobial resistance was particularly observed in isolates from male patients who had sex with men or from patients that had travelled to Asia. Furthermore, isolates related to international clusters were also circulating in the Netherlands. Travel-related isolates formed clusters with isolates from patients without travel history, indicating their emergence into the Dutch population. Conclusions: In conclusion, laboratory surveillance using whole genome sequencing for genetic characterization of isolates complements the current epidemiological surveillance, as the latter is not sufficient to detect all (inter)national clusters, emphasizing the importance of multifactorial public health approaches.
Published: 2019

40. Intellectual Disability-related genes increase ADHD risk and locomotor activity in Drosophila

Author: Ditte Demontis, Anna Castells-Nobau, Annette Schenck, Monique van der Voet, Euginia L. Singgih, Barbara Franke, Marieke Klein, Anders D. Børglum, Lambertus A. Kiemeney, Nina Roth Mota, Anne van Rens, Han G. Brunner, and Alejandro Arias-Vasquez
Subjects: Genetics, 0303 health sciences, Gene knockdown, Candidate gene, biology, Dopaminergic, Genomics, medicine.disease, biology.organism_classification, 03 medical and health sciences, 0302 clinical medicine, mental disorders, Intellectual disability, medicine, Drosophila melanogaster, Allele, Gene, 030217 neurology & neurosurgery, 030304 developmental biology
Abstract: ObjectiveAttention-Deficit/Hyperactivity Disorder (ADHD) is a common, highly heritable neuropsychiatric disorder. ADHD often co-occurs with Intellectual Disability (ID), and shared overlapping genetics have been suggested. This study aimed to identify novel ADHD genes by investigating whether genes carrying rare mutations linked to ID contribute to ADHD risk through common genetic variants. Validation and characterization of candidates were performed using Drosophila melanogaster.MethodCommon genetic variants in a diagnostic gene panel of 396 autosomal ID genes were tested for association with ADHD risk, through gene-set and gene-wide analyses, using ADHD meta-analytic data of the Psychiatric Genomics Consortium (n=19,210) for discovery and iPSYCH ADHD data for replication (n=37,076). The significant genes were functionally validated and characterized in Drosophila by assessing locomotor activity and sleep upon knockdown of those genes in brain circuits.ResultsThe ID gene-set was significantly associated with ADHD risk in the discovery and replication data-sets. The three genes most consistently associated were MEF2C, ST3GAL3, and TRAPPC9. Performing functional characterization of the two evolutionary conserved genes in Drosophila melanogaster, we found their knockdown in dopaminergic (dMEF2) and circadian neurons (dTRAPPC9) to result in increased locomotor activity and reduced sleep, concordant with the human phenotype.ConclusionsThis study reveals that a large set of ID-related genes contributes to ADHD risk through effects of common alleles. Utilizing this continuity, we identified TRAPPC9, MEF2C, and ST3GAL3 as novel ADHD candidate genes. Characterization in Drosophila suggests that TRAPPC9 and MEF2C contribute to ADHD-related behavior through distinct neural substrates.
Published: 2019

41. Assessment of fibroblast nuclear morphology aids interpretation of LMNA variants

Author: Frans C. S. Ramaekers, Arthur van den Wijngaard, Ingrid P.C. Krapels, Miriam A.F. Kamps, Han G. Brunner, Florence H J van Tienen, Patrick J. Lindsey, Jos L. V. Broers, Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA KG Lab Centraal Lab (9), MUMC+: DA KG Polikliniek (9), RS: GROW - R2 - Basic and Translational Cancer Biology, Moleculaire Celbiologie, MUMC+: DA Klinische Genetica (5), RS: Carim - B06 Imaging, and RS: CARIM - R2 - Cardiac function and failure
Subjects: EXPRESSION, Pathology, medicine.medical_specialty, congenital, hereditary, and neonatal diseases and abnormalities, Laminopathy, Biology, LAMIN A/C MUTATIONS, PHENOTYPE, Article, LMNA, 03 medical and health sciences, Cytogenetics, All institutes and research themes of the Radboud University Medical Center, Genetics, medicine, Humans, PRELAMIN, Genetic Testing, Fibroblast, Genetics (clinical), Cells, Cultured, Cell Nucleus, 0303 health sciences, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], integumentary system, Genetic heterogeneity, 030305 genetics & heredity, Fibroblasts, PROGERIA-SYNDROME, medicine.disease, Lamin Type A, DILATED CARDIOMYOPATHY, GENE, MUSCULAR-DYSTROPHY, Cell nucleus, medicine.anatomical_structure, ENVELOPE ALTERATIONS, embryonic structures, PARTIAL LIPODYSTROPHY, Immunostaining, Lamin
Abstract: The phenotypic heterogeneity of Lamin A/C (LMNA) variants renders it difficult to classify them. As a consequence, many LMNA variants are classified as variant of unknown significance (VUS). A number of studies reported different types of visible nuclear abnormalities in LMNA-variant carriers, such as herniations, honeycomb-like structures and irregular Lamin staining. In this study, we used lamin A/C immunostaining and nuclear DAPI staining to assess the number and type of nuclear abnormalities in primary dermal fibroblast cultures of laminopathy patients and healthy controls. The total number of abnormal nuclei, which includes herniations, honeycomb-structures, and donut-like nuclei, was found to be the most discriminating parameter between laminopathy and control cell cultures. The percentage abnormal nuclei was subsequently scored in fibroblasts of 28 LMNA variant carriers, ranging from (likely) benign to (likely) pathogenic variant. Using this method, 27 out of 28 fibroblast cell cultures could be classified as either normal (n = 14) or laminopathy (n = 13) and no false positive results were obtained. The obtained specificity was 100% (CI 40-100%) and sensitivity 77% (46-95%). We conclude that assessing the percentage of abnormal nuclei is a quick and reliable method, which aids classification or confirms pathogenicity of identified LMNA variants causing formation of aberrant lamin A/C protein.
Published: 2019

42. Mutations in ACTL6B Cause Neurodevelopmental Deficits and Epilepsy and Lead to Loss of Dendrites in Human Neurons

Author: Jacques L. Michaud, Jessica Sebastian, Hanrong Wu, Dick Lindhout, Karla Manzano-Vargas, Nuwan C. Hettige, Ingrid M. Wentzensen, Huashan Peng, Amy Crunk, Heika Silviera, Malvin Jefri, Henry Houlden, Fadi F. Hamdan, Zahia Aouabed, Stephanie Efthymiou, Xin Zhang, Renske Oegema, Arnaud Tanti, Jerry Vockley, Gustavo Turecki, Julien van Gils, Amber G. Begtrup, Christina Nassif, Gunnar Houge, Naomichi Matsumoto, Thomas Bourgeron, Jean-François Théroux, Emily Fassi, Noriko Miyake, Robert D. Nicholls, Jose E. Martinez, Kristin Herman, Lilit Antonyan, Philippe M. Campeau, Margaret G. Au, Dominic Nelson, Vincenzo Salpietro, Scott C. Bell, Pierre Priam, Joshua L. Deignan, Gregory M. Cooper, Rune Østern, Han G. Brunner, Dagmar Huhle, Amy Goldstein, John M. Graham, Christine Coubes, Koen L.I. van Gassen, Tabib Dabir, Maria Hafström, Simon Gravel, Sophie Ehresmann, Elsa Rossignol, Ilaria Kolobova, Walla Al-Hertani, Julie A. Lessard, Lionel Carmant, Sonja Martin, Richard Delorme, Carl Ernst, Jolien S. Klein Wassink-Ruiter, Naguib Mechawar, Yoshio Makita, Candice R. Finnila, Rami Abou Jamra, Anne Lortie, Justine Rousseau, Sarju G. Mehta, Lina Ghaloul-Gonzalez, MUMC+: DA Klinische Genetica (5), Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, McGill University = Université McGill [Montréal, Canada], Université de Montréal (UdeM), University of Pittsburgh (PITT), Pennsylvania Commonwealth System of Higher Education (PCSHE), GeneDx [Gaithersburg, MD, USA], University of California [Davis] (UC Davis), University of California, David Geffen School of Medicine [Los Angeles], University of California [Los Angeles] (UCLA), University of California-University of California, University of Calgary, UCL, Institute of Neurology [London], Yokohama City University (YCU), Asahikawa Medical College, Trondheim University, Haukeland University Hospital, University of Bergen (UiB), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), University of Groningen [Groningen], University Medical Center Groningen [Groningen] (UMCG), Children's Hospital of Pittsburgh of UPMC [Etats-Unis], Belfast City Hospital, Génétique humaine et fonctions cognitives - Human Genetics and Cognitive Functions (GHFC (UMR_3571 / U-Pasteur_1)), Institut Pasteur [Paris]-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Child and Adolescent Psychiatry Department [AP- HP Hôpital Robert Debré], AP-HP Hôpital universitaire Robert-Debré [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), HudsonAlpha Institute for Biotechnology [Huntsville, AL], Children’s Rehabilitation Service [Mobile, AL] (CRS), Children's Rehabilitation Service [Montgomery, AL] (CRS), University Medical Center [Utrecht], Cambridge University Hospitals - NHS (CUH), University of Cambridge [UK] (CAM), University Hospital Leipzig, Donders Institute for Brain, Cognition and Behaviour, Radboud university [Nijmegen], Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], Cedars-Sinai Medical Center, CHU Montpellier, Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), We acknowledge funding by FRQS doctoral (S.B.), Indonesian Endowment Fund for Education PhD award (M.J.), CONACYT (Mexico) and MITACS (K.M.V.), Genome Canada and Génome Québec (J.L.M. and E.R.), Canada Research Chairs program (G.T. and C.E.), AMED, MEXT, JST, MHLW, and Takeda Science Foundation (N. Matsumoto), and CIHR grant (C.E. and P.M.C.)., University of California (UC), University of California (UC)-University of California (UC), Institut Pasteur [Paris] (IP)-Université Paris Diderot - Paris 7 (UPD7)-Centre National de la Recherche Scientifique (CNRS), Radboud University [Nijmegen], and Faculteit Medische Wetenschappen/UMCG
Subjects: 0301 basic medicine, Male, PROTEIN EXPRESSION, Chromosomal Proteins, Non-Histone, Mutant, MESH: Neurons, 0302 clinical medicine, SYNAPTIC PLASTICITY, MESH: Child, Genetics(clinical), Global developmental delay, TRANSCRIPTION, Child, Genetics (clinical), ACTL6B, genetic engineering, intellectual disability, neurodevelopment, seizure, stem cells, Genetics, Neurons, SWI/SNF COMPLEX, MESH: Infant, Hypotonia, Neural stem cell, Chromatin, DNA-Binding Proteins, medicine.anatomical_structure, MESH: Young Adult, MESH: Epilepsy, Child, Preschool, Female, medicine.symptom, Adult, MESH: Mutation, DISORDERS, Induced Pluripotent Stem Cells, Biology, MESH: Induced Pluripotent Stem Cells, MESH: Actins, MESH: Dendrites, Chromatin remodeling, Article, MESH: Chromatin, 03 medical and health sciences, Young Adult, All institutes and research themes of the Radboud University Medical Center, MESH: Chromosomal Proteins, Non-Histone, medicine, Journal Article, Humans, CHROMATIN REMODELING COMPLEX, Progenitor cell, Loss function, MESH: Neurodevelopmental Disorders, MESH: Humans, Epilepsy, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], [SCCO.NEUR]Cognitive science/Neuroscience, MESH: Child, Preschool, COFFIN-SIRIS SYNDROME, MEMORY, Infant, MESH: Adult, Dendrites, GENE, MESH: Male, Actins, 030104 developmental biology, Neurodevelopmental Disorders, Mutation, OLIGODENDROCYTE, Neuron, MESH: Female, 030217 neurology & neurosurgery, MESH: DNA-Binding Proteins
Abstract: International audience; We identified individuals with variations in ACTL6B, a component of the chromatin remodeling machinery including the BAF complex. Ten individuals harbored bi-allelic mutations and presented with global developmental delay, epileptic encephalopathy, and spasticity, and ten individuals with de novo heterozygous mutations displayed intellectual disability, ambulation deficits, severe language impairment, hypotonia, Rett-like stereotypies, and minor facial dysmorphisms (wide mouth, diastema, bulbous nose). Nine of these ten unrelated individuals had the identical de novo c.1027G>A (p.Gly343Arg) mutation. Human-derived neurons were generated that recaptured ACTL6B expression patterns in development from progenitor cell to post-mitotic neuron, validating the use of this model. Engineered knock-out of ACTL6B in wild-type human neurons resulted in profound deficits in dendrite development, a result recapitulated in two individuals with different bi-allelic mutations, and reversed on clonal genetic repair or exogenous expression of ACTL6B. Whole-transcriptome analyses and whole-genomic profiling of the BAF complex in wild-type and bi-allelic mutant ACTL6B neural progenitor cells and neurons revealed increased genomic binding of the BAF complex in ACTL6B mutants, with corresponding transcriptional changes in several genes including TPPP and FSCN1, suggesting that altered regulation of some cytoskeletal genes contribute to altered dendrite development. Assessment of bi-alleic and heterozygous ACTL6B mutations on an ACTL6B knock-out human background demonstrated that bi-allelic mutations mimic engineered deletion deficits while heterozygous mutations do not, suggesting that the former are loss of function and the latter are gain of function. These results reveal a role for ACTL6B in neurodevelopment and implicate another component of chromatin remodeling machinery in brain disease.
Published: 2019

43. Exploration of Shared Genetic Architecture Between Subcortical Brain Volumes and Anorexia Nervosa

Author: Walton, E, Hibar, D, Yilmaz, Z, Jahanshad, N, Cheung, J, Batury, V-L, Seitz, J, Bulik, CM, Thompson, PM, Ehrlich, Stefan, Hibar, Derrek P, Stein, Jason L, Renteria, Miguel E, Arias-Vasquez, Alejandro, Desrivieres, Sylvane, Jahanshad, Neda, Toro, Roberto, Wittfeld, Katharina, Abramovic, Lucija, Andersson, Micael, Aribisala, Benjamin S, Armstrong, Nicola J, Bernard, Manon, Bohlken, Marc M, Boks, Marco P, Bralten, Janita, Brown, Andrew A, Chakravarty, M Mallar, Chen, Qiang, Ching, Christopher RK, Cuellar-Partida, Gabriel, Den Braber, Anouk, Giddaluru, Sudheer, Goldman, Aaron L, Grimm, Oliver, Guadalupe, Tulio, Hass, Johanna, Woldehawariat, Girma, Holmes, Avram J, Hoogman, Martine, Janowitz, Deborah, Jia, Tianye, Kim, Sungeun, Klein, Marieke, Kraemer, Bernd, Lee, Phil H, Loohuis, Loes M Olde, Luciano, Michelle, Macare, Christine, Mather, Karen A, Mattheisen, Manuel, Milaneschi, Yuri, Nho, Kwangsik, Papmeyer, Martina, Ramasamy, Adaikalavan, Risacher, Shannon L, Roiz-Santianez, Roberto, Rose, Emma J, Salami, Alireza, Samann, Philipp G, Schmaal, Lianne, Schork, Andrew J, Shin, Jean, Strike, Lachlan T, Teumer, Alexander, van Donkelaar, Marjolein MJ, van Eijk, Kristel R, Walters, Raymond K, Westlye, Lars T, Whelan, Christopher D, Winkler, Anderson M, Zwiers, Marcel P, Alhusaini, Saud, Athanasiu, Lavinia, Hakobjan, Marina MH, Hartberg, Cecilie B, Haukvik, Unn K, Heister, Angelien JGAM, Hohn, David, Kasperaviciute, Dalia, Liewald, David CM, Lopez, Lorna M, Makkinje, Remco RR, Matarin, Mar, Naber, Marlies AM, Mckay, David R, Needham, Margaret, Nugent, Allison C, Putz, Benno, Shen, Li, Sprooten, Emma, Trabzuni, Daniah, van der Marel, Saskia SL, van Hulzen, Kimm JE, Walton, Esther, Wolf, Christiane, Almasy, Laura, Ames, David, Arepalli, Sampath, Assareh, Amelia A, Bastin, Mark E, Brodaty, Henry, Bulayeva, Kazima B, Carless, Melanie A, Cichon, Sven, Corvin, Aiden, Curran, Joanne E, Czisch, Michael, de Zubicaray, Greig I, Dillman, Allissa, Duggirala, Ravi, Dyer, Thomas D, Erk, Susanne, Fedko, Iryna O, Ferrucci, Luigi, Foroud, Tatiana M, Fox, Peter T, Fukunaga, Masaki, Gibbs, J Raphael, Goring, Harald HH, Green, Robert C, Guelfi, Sebastian, Hansell, Narelle K, Hartman, Catharina A, Hegenscheid, Katrin, Heinz, Andreas, Hernandez, Dena G, Heslenfeld, Dirk J, Hoekstra, Pieter J, Holsboer, Florian, Homuth, Georg, Hottenga, Jouke-Jan, Ikeda, Masashi, Jr, Jack Clifford R, Jenkinson, Mark, Johnson, Robert, Kanai, Ryota, Keil, Maria, Jr, Kent Jack W, Kochunov, Peter, Kwok, John B, Lawrie, Stephen M, Liu, Xinmin, Longo, Dan L, McMahon, Katie L, Meisenzahl, Eva, Melle, Ingrid, Mohnke, Sebastian, Montgomery, Grant W, Mostert, Jeanette C, Muhleisen, Thomas W, Nalls, Michael A, Nichols, Thomas E, Nilsson, Lars G, Nothen, Markus M, Ohi, Kazutaka, Olvera, Rene L, Perez-Iglesias, Rocio, Pike, G Bruce, Potkin, Steven G, Reinvang, Ivar, Reppermund, Simone, Rietschel, Marcella, Romanczuk-Seiferth, Nina, Rosen, Glenn D, Rujescu, Dan, Schnell, Knut, Schofield, Peter R, Smith, Colin, Steen, Vidar M, Sussmann, Jessika E, Thalamuthu, Anbupalam, Toga, Arthur W, Traynor, Bryan J, Troncoso, Juan, Turner, Jessica A, Hernandez, Maria C Valdes, van't Ent, Dennis, van der Brug, Marcel, van der Wee, Nic JA, van Tol, Marie-Jose, Veltman, Dick J, Wassink, Thomas H, Westman, Eric, Zielke, Ronald H, Zonderman, Alan B, Ashbrook, David G, Hager, Reinmar, Lu, Lu, McMahon, Francis J, Morris, Derek W, Williams, Robert W, Brunner, Han G, Buckner, Randy L, Buitelaar, Jan K, Cahn, Wiepke, Calhoun, Vince D, Cavalleri, Gianpiero L, Crespo-Facorro, Benedicto, Dale, Anders M, Davies, Gareth E, Delanty, Norman, Depondt, Chantal, Djurovic, Srdjan, Drevets, Wayne C, Espeseth, Thomas, Gollub, Randy L, Ho, Beng-Choon, Hoffmann, Wolfgang, Hosten, Norbert, Kahn, Rene S, Le Hellard, Stephanie, Meyer-Lindenberg, Andreas, Mueller-Myhsok, Bertram, Nauck, Matthias, Nyberg, Lars, Pandolfo, Massimo, Penninx, Brenda WJH, Roffman, Joshua L, Sisodiya, Sanjay M, Smoller, Jordan W, van Bokhoven, Hans, van Haren, Neeltje EM, Volzke, Henry, Walter, Henrik, Weiner, Michael W, Wen, Wei, White, Tonya, Agartz, Ingrid, Andreassen, Ole A, Blangero, John, Boomsma, Dorret I, Brouwer, Rachel M, Cannon, Dara M, Cookson, Mark R, de Geus, Eco JC, Deary, Ian J, Donohoe, Gary, Fernandez, Guillen, Fisher, Simon E, Francks, Clyde, Glahn, David C, Grabe, Hans J, Gruber, Oliver, Hardy, John, Hashimoto, Ryota, Pol, Hilleke E Hulshoff, Jonsson, Erik G, Kloszewska, Iwona, Lovestone, Simon, Mattay, Venkata S, Mecocci, Patrizia, McDonald, Colm, McIntosh, Andrew M, Ophoff, Roel A, Paus, Tomas, Pausova, Zdenka, Ryten, Mina, Sachdev, Perminder S, Saykin, Andrew J, Simmons, Andrew, Singleton, Andrew, Soininen, Hilkka, Wardlaw, Joanna M, Weale, Michael E, Weinberger, Daniel R, Adams, Hieab HH, Launer, Lenore J, Seiler, Stephan, Schmidt, Reinhold, Chauhan, Ganesh, Satizabal, Claudia L, Becker, James T, Yanek, Lisa R, van der Lee, Sven J, Ebling, Maritza, Fischl, Bruce, Longstreth, WT, Greve, Douglas, Schmidt, Helena, Nyquist, Paul, Vinke, Louis N, van Duijn, Cornelia M, Luting, Xue, Mazoyer, Bernard, Bis, Joshua C, Gudnason, Vilmundur, Seshadri, Sudha, Ikram, M Arfan, Martin, Nicholas G, Wright, Margaret J, Schumann, Gunter, Franke, Barbara, Thompson, Paul M, Medland, Sarah E, Duncan, Laramie, Yilmaz, Zeynep, Walters, Raymond, Goldstein, Jackie, Anttila, Verneri, Bulik-Sullivan, Brendan, Ripke, Stephan, Adan, Roger, Alfredsson, Lars, Ando, Tetsuya, Andreassen, Ole, Aschauer, Harald, Baker, Jessica, Barrett, Jeffrey, Bencko, Vladimir, Bergen, Andrew, Berrettini, Wade, Birgegard, Andreas, Boni, Claudette, Perica, Vesna Boraska, Brandt, Harry, Burghardt, Roland, Carlberg, Laura, Cassina, Matteo, Cichon, Carolyn Cesta Sven, Clementi, Maurizio, Cohen-Woods, Sarah, Coleman, Joni, Cone, Roger, Courtet, Philippe, Crawford, Steven, Crow, Scott, Crowley, Jim, Danner, Unna, Davis, Oliver, de Zwaan, Martina, Dedoussis, George, Degortes, Daniela, DeSocio, Janiece, Dick, Danielle, Dikeos, Dimitris, Dina, Christian, Ding, Bo, Dmitrzak-Weglarz, Monika, Docampo, Elisa, Egberts, Karin, Escaramis, Georgia, Esko, Tonu, Estivill, Xavier, Favaro, Angela, Fernandez-Aranda, Fernando, Fichter, Manfred, Finan, Chris, Fischer, Krista, Floyd, James, Focker, Manuel, Foretova, Lenka, Forzan, Monica, Fox, Caroline, Franklin, Christopher, Gallinger, Valerie Gaborieau Steven, Gambaro, Giovanni, Gaspar, Helena, Giegling, Ina, Gonidakis, Fragiskos, Gorwood, Philip, Gratacos, Monica, Guillaume, Sebastien, Guo, Yiran, Hakonarson, Hakon, Halmi, Katherine, Harrison, Rebecca, Hatzikotoulas, Konstantinos, Hauser, Joanna, Hebebrand, Johannes, Helder, Sietske, Hendriks, Judith, Herms, Stefan, Herpertz-Dahlmann, Beate, Herzog, Wolfgang, Hilliard, Christopher, Huckins, Laura, Hudson, James, Huemer, Julia, Imgart, Hartmut, Inoko, Hidetoshi, Jamain, Sigrid Jall Stephane, Janout, Vladimir, Jimenez-Murcia, Susana, Johnson, Craig, Jordan, Jenny, Julia, Antonio, Jureus, Anders, Kalsi, Gursharan, Kaplan, Allan, Kaprio, Jaakko, Karhunen, Leila, Karwautz, Andreas, Kas, Martien, Kaye, Walter, Kennedy, Martin, Kennedy, James, Keski-Rahkonen, Anna, Kiezebrink, Kirsty, Kim, Youl-Ri, Klareskog, Lars, Klump, Kelly, Knudsen, Gun Peggy, Koeleman, Bobby, Koubek, Doris, La Via, Maria, Landen, Mikael, Leboyer, Marion, Levitan, Robert, Li, Dong, Lichtenstein, Paul, Lilenfeld, Lisa, Lissowska, Jolanta, Lundervold, Astri, Magistretti, Pierre, Maj, Mario, Mannik, Katrin, Marsal, Sara, Kaminska, Debora, Martin, Nicholas, Mattingsdal, Morten, McDevitt, Sara, McGuffin, Peter, Merl, Elisabeth, Metspalu, Andres, Meulenbelt, Ingrid, Micali, Nadia, Mitchell, James, Mitchell, Karen, Monteleone, Palmiero, Monteleone, Alessio Maria, Montgomery, Grant, Mortensen, Preben, Munn-Chernoff, Melissa, Mueller, Timo, Nacmias, Benedetta, Navratilova, Marie, Nilsson, Ida, Norring, Claes, Ntalla, Ioanna, Ophoff, Roel, O'Toole, Julie, Palotie, Aarno, Pantel, Jacques, Papezova, Hana, Pinto, Richard Parker Dalila, Rabionet, Raquel, Raevuori, Anu, Rajewski, Andrzej, Ramoz, Nicolas, Rayner, N William, Reichborn-Kjennerud, Ted, Ricca, Valdo, Ripatti, Samuli, Ritschel, Franziska, Roberts, Marion, Rotondo, Alessandro, Rybakowski, Filip, Santonastaso, Paolo, Scherag, Andre, Scherer, Stephen, Schmidt, Ulrike, Schork, Nicholas, Schosser, Alexandra, Scott, Laura, Seitz, Jochen, Slachtova, Lenka, Sladek, Robert, Slagboom, P Eline, Slof-Op't Landt, Margarita, Slopien, Agnieszka, Smith, Tosha, Soranzo, Nicole, Sorbi, Sandro, Southam, Lorraine, Steen, Vidar, Strengman, Eric, Strober, Michael, Szatkiewicz, Jin, Szeszenia-Dabrowska, Neonila, Tachmazidou, Ioanna, Tenconi, Elena, Tortorella, Alfonso, Tozzi, Federica, Treasure, Janet, Tschop, Matthias, Tsitsika, Artemis, Tziouvas, Konstantinos, van Elburg, Annemarie, van Furth, Eric, Wade, Tracey, Wagner, Gudrun, Watson, Hunna, Wichmann, H-Erich, Widen, Elisabeth, Woodside, D Blake, Yanovski, Jack, Yao, Shuyang, Zerwas, Stephanie, Zipfel, Stephan, Thornton, Laura, Hinney, Anke, Breen, Gerome, Bulik, Cynthia M, PGC-ED, Grp, ENIGMA Genetics Working, Interdisciplinary Centre Psychopathology and Emotion regulation (ICPE), Kas lab, Clinical Cognitive Neuropsychiatry Research Program (CCNP), Psychiatry, Amsterdam Neuroscience - Complex Trait Genetics, and APH - Mental Health
Subjects: 0301 basic medicine, Anorexia Nervosa, Eating Disorders, REWARD CIRCUITRY, Genome-wide association study, ADOLESCENT, PGC-ED, Bioinformatics, Linkage Disequilibrium, 0302 clinical medicine, Anorexia nervosa, Brain structure, Genetic correlation, SCHIZOPHRENIA, ENIGMA Genetics Working Group, 2.1 Biological and endogenous factors, Psychology, Aetiology, Cervell, RISK, ABNORMALITIES, Anorèxia nerviosa, Brain, FUNCTIONAL CONNECTIVITY, Organ Size, Single Nucleotide, Serious Mental Illness, Magnetic Resonance Imaging, 3. Good health, Anorexia, Mental Health, Neurology, Anorexia nervosa (differential diagnoses), Brain size, MENDELIAN RANDOMIZATION, Biomedical Imaging, Cognitive Sciences, RESPONSE-INHIBITION, Neuroscience (miscellaneous), Biology, Polymorphism, Single Nucleotide, Article, 03 medical and health sciences, Cellular and Molecular Neuroscience, Mendelian randomization, Journal Article, Genetics, Humans, Genetic Testing, GENOME-WIDE ASSOCIATION, Polymorphism, POLYMORPHISMS, Genetic association, Neurology & Neurosurgery, Prevention, Human Genome, Neurosciences, Mendelian Randomization Analysis, Genetic architecture, Brain Disorders, 030104 developmental biology, Genetic marker, Case-Control Studies, 030217 neurology & neurosurgery, Genètica, Genome-Wide Association Study
Abstract: Molecular neurobiology 56(7), 5146-5156 (2019). doi:10.1007/s12035-018-1439-4, Published by Humana Press, Totowa, NJ
Published: 2019

44. Non-Syndromic Cleft Lip with or without Cleft Palate: Genome-Wide Association Study in Europeans Identifies a Suggestive Risk Locus at 16p12.1 and Supports SH3PXD2A as a Clefting Susceptibility Gene

Author: Elisabeth Mangold, Nel Roeleveld, Julia Welzenbach, Khalid Aldhorae, Lambertus A. Kiemeney, Iris A.L.M. van Rooij, Stefaan J. Bergé, Han G. Brunner, Joris Vermeesch, Kerstin U. Ludwig, Tessel E. Galesloot, Greet Hens, Michelle Thonissen, Titiaan Dormaar, Nina Ishorst, Edwin M. Ongkosuwito, Augusto Rojas-Martinez, Carine Carels, Koen Devriendt, Michael Knapp, MUMC+: DA Klinische Genetica (5), Klinische Genetica, and RS: GROW - R4 - Reproductive and Perinatal Medicine
Subjects: 0301 basic medicine, Male, Candidate gene, Genome-wide association study, 030105 genetics & heredity, VARIANTS, CANDIDATE GENES, Mice, Belgium, Risk Factors, IRF6, Zebrafish, Genetics (clinical), Netherlands, Genetics, Genetics & Heredity, Mice, Knockout, biology, NONSYNDROMIC OROFACIAL CLEFTS, Cleft Palate, Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], Knockout mouse, Female, Life Sciences & Biomedicine, Cleft Lip, congenital malformation, Locus (genetics), GENOTYPE IMPUTATION, Article, 03 medical and health sciences, Animals, Humans, METAANALYSES, orofacial cleft, Gene, Science & Technology, genome-wide association study, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Chromosomes, Human, Pair 10, biology.organism_classification, Reconstructive and regenerative medicine Radboud Institute for Health Sciences [Radboudumc 10], Adaptor Proteins, Vesicular Transport, cleft lip with or without cleft palate, 030104 developmental biology, Etiology, Non syndromic, Chromosomes, Human, Pair 16, FOXE1
Abstract: Non-syndromic cleft lip with or without cleft palate (nsCL/P) ranks among the most common human congenital malformations, and has a multifactorial background in which both exogenous and genetic risk factors act in concert. The present report describes a genome-wide association study (GWAS) involving a total of 285 nsCL/P patients and 1212 controls from the Netherlands and Belgium. Twenty of the 40 previously reported nsC/LP susceptibility loci were replicated, which underlined the validity of this sample. SNV-based analysis of the data identified an as yet unreported suggestive locus at chromosome 16p12.1 (p-value of the lead SNV: 4.17 &times, 10&minus, 7). This association was replicated in two of three patient/control replication series (Central European and Yemeni). Gene analysis of the GWAS data prioritized SH3PXD2A at chromosome 10q24.33 as a candidate gene for nsCL/P. To date, support for this gene as a cleft gene has been restricted to data from zebrafish and a knockout mouse model. The present GWAS was the first to implicate SH3PXD2A in non-syndromic cleft formation in humans. In summary, although performed in a relatively small sample, the present GWAS generated novel insights into nsCL/P etiology.
Published: 2019

45. Exome chip association study excluded the involvement of rare coding variants with large effect sizes in the etiology of anorectal malformations

Author: Erwin Brosens, Heiko Reutter, Han G. Brunner, Sophie A. C. Holsink, Charlotte H. W. Wijers, Ekkehart Jenetzky, Romy van de Putte, Maria-Mercè Garcia-Barceló, Nel Roeleveld, Marloes Steehouwer, Paul M. A. Broens, Robert M.W. Hofstra, Paul K.H. Tam, Carlo Marcelis, Lambertus A. Kiemeney, Nadine Zwink, Sita H. Vermeulen, Maartje van de Vorst, Alice S. Brooks, Annelies de Klein, Tessel E. Galesloot, Cornelius E. J. Sloots, Michael Ludwig, Ivo de Blaauw, Loes F.M. van der Zanden, Markus Homberg, Iris A.L.M. van Rooij, Rocio Acuna-Hidalgo, MUMC+: DA Klinische Genetica (5), Klinische Genetica, RS: GROW - R4 - Reproductive and Perinatal Medicine, Clinical Genetics, and Pediatric Surgery
Subjects: Male, ANOMALIES, Candidate gene, Heredity, Etiology, Molecular biology, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Pathology and Laboratory Medicine, Sequencing techniques, EXCLUSION, Medicine and Health Sciences, Exome, DNA sequencing, Oligonucleotide Array Sequence Analysis, Genetics, Sanger sequencing, RISK, education.field_of_study, Multidisciplinary, Congenital Anomalies, Anorectal Malformations, Genetic Mapping, Reconstructive and regenerative medicine Radboud Institute for Molecular Life Sciences [Radboudumc 10], Urological cancers Radboud Institute for Health Sciences [Radboudumc 15], OBESITY, symbols, Engineering and Technology, Medicine, Female, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Research Article, Adult, Quality Control, CANDIDATE GENE, Science, Population, Variant Genotypes, Biology, symbols.namesake, Signs and Symptoms, Diagnostic Medicine, Industrial Engineering, BIRTH-DEFECTS, Congenital Disorders, Humans, Allele, education, Gene, Alleles, Fistulas, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Dideoxy DNA sequencing, Genetic Variation, Biology and Life Sciences, Human Genetics, Reconstructive and regenerative medicine Radboud Institute for Health Sciences [Radboudumc 10], Research and analysis methods, Molecular biology techniques, Bonferroni correction, FGF10, Genetic Loci, REGISTRY, Renal disorders Radboud Institute for Health Sciences [Radboudumc 11]
Abstract: IntroductionAnorectal malformations (ARM) are rare congenital malformations, resulting from disturbed hindgut development. A genetic etiology has been suggested, but evidence for the involvement of specific genes is scarce. We evaluated the contribution of rare and low-frequency coding variants in ARM etiology, assuming a multifactorial model.MethodsWe analyzed 568 Caucasian ARM patients and 1,860 population-based controls using the Illumina Human Exome Beadchip array, which contains >240,000 rare and low-frequency coding variants. GenomeStudio clustering and calling was followed by re-calling of 'no-calls' using zCall for patients and controls simultaneously. Single variant and gene-based analyses were performed to identify statistically significant associations, applying Bonferroni correction. Following an extra quality control step, candidate variants were selected for validation using Sanger sequencing.ResultsWhen we applied a MAF of >= 1.0%, no variants or genes showed statistically significant associations with ARM. Using a MAF cut-off at 0.4%, 13 variants initially reached statistical significance, but had to be discarded upon further inspection: ten variants represented calling errors of the software, while the minor alleles of the remaining three variants were not confirmed by Sanger sequencing.ConclusionOur results show that rare and low-frequency coding variants with large effect sizes, present on the exome chip do not contribute to ARM etiology.
Published: 2019

46. Recurrent Mutations in the Basic Domain of TWIST2 Cause Ablepharon Macrostomia and Barber-Say Syndromes

Author: Elise Valkanas, Hon-Yin Brian Chung, Peter Farndon, Patricia M. Zerfas, Oliver Bartsch, Martin Zenker, Jeroen Bakkers, Alexander Hoischen, Feliciano J. Ramos, Eva Bermejo-Sánchez, Haigen Huang, Gijs van Haaften, Lynne A. Wolfe, Taylor Davis, Eduarda Morgana da Silva, Han G. Brunner, W. K. Jacyk, Bruno Dallapiccola, Laura Mazzanti, Cathy A. Stevens, Mieke M. van Haelst, Hanka Venselaar, Cornelius F. Boerkoel, Francesco Brancati, Cynthia J. Tifft, May Christine V. Malicdan, Nathalie Roche, Bert B.A. de Vries, Victor Evangelista de Faria Ferraz, Chyi-Chia Richard Lee, Brian P. Brooks, Farahnaz Sabbagh-Kermani, Federico Tessadori, Denny Schanze, Barbara N. Pusey, Ariana Kariminejad, Valerie Maduro, Janice Lee, Giovanna Zambruno, Shuo Lin, Cédric Le Caignec, Thomas C. Markello, Maria Tsokos, Shannon Marchegiani, Fabiana Martins, William A. Gahl, Anneke T. Vulto-van Silfhout, Other departments, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, Amsterdam Reproduction & Development (AR&D), MUMC+: DA Klinische Genetica (5), RS: GROW - Developmental Biology, RS: GROW - R4 - Reproductive and Perinatal Medicine, Marchegiani, Shannon, Davis, Taylor, Tessadori, Federico, Van Haaften, Gij, Brancati, Francesco, Hoischen, Alexander, Huang, Haigen, Valkanas, Elise, Pusey, Barbara, Schanze, Denny, Venselaar, Hanka, Vulto-Van Silfhout, Anneke T., Wolfe, Lynne A., Tifft, Cynthia J., Zerfas, Patricia M., Zambruno, Giovanna, Kariminejad, Ariana, Sabbagh-Kermani, Farahnaz, Lee, Janice, Tsokos, Maria G., Lee, Chyi-Chia R., Ferraz, Victor, Da Silva, Eduarda Morgana, Stevens, Cathy A., Roche, Nathalie, Bartsch, Oliver, Farndon, Peter, Bermejo-Sanchez, Eva, Brooks, Brian P., Maduro, Valerie, Dallapiccola, Bruno, Ramos, Feliciano J., Chung, Hon-Yin Brian, Le Caignec, Cédric, Martins, Fabiana, Jacyk, Witold K., Mazzanti, Laura, Brunner, Han G., Bakkers, Jeroen, Lin, Shuo, Malicdan, May Christine V., Boerkoel, Cornelius F., Gahl, William A., De Vries, Bert B.A., Van Haelst, Mieke M., Zenker, Martin, Markello, Thomas C., and Hubrecht Institute for Developmental Biology and Stem Cell Research
Subjects: Models, Molecular, Candidate gene, Hirsutism, Protein Conformation, HeLa Cell, medicine.disease_cause, Transcriptome, Twist transcription factor, Models, Genetics(clinical), Exome, Eye Abnormalities, Non-U.S. Gov't, Genetics (clinical), Zebrafish, Genetics, Mutation, Microscopy, Macrostomia, Setleis syndrome, Hypertelorism, Research Support, Non-U.S. Gov't, Hypertrichosi, Eyelid Disease, GENÉTICA, Phenotype, Eyelid Diseases, Abnormalities, Multiple, Sequence Analysis, Human, Chromatin Immunoprecipitation, Molecular Sequence Data, Mutation, Missense, Hypertrichosis, Amino Acid Sequence, Animals, Base Sequence, HeLa Cells, Humans, Electron, Missense, Repressor Proteins, DNA, Skin Abnormalities, Twist Transcription Factor, Molecular, Other Research Radboud Institute for Molecular Life Sciences [Radboudumc 0], Biology, Research Support, Article, Frameshift mutation, Genetic, Ablepharon macrostomia syndrome, Skin Abnormalitie, medicine, Journal Article, Abnormalities, Multiple, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Animal, Twist-Related Protein 1, Sequence Analysis, DNA, Repressor Protein, medicine.disease, Eye Abnormalitie, Microscopy, Electron, sense organs, Nanomedicine Radboud Institute for Molecular Life Sciences [Radboudumc 19]
Abstract: Contains fulltext : 153827.pdf (Publisher’s version ) (Open Access) Ablepharon macrostomia syndrome (AMS) and Barber-Say syndrome (BSS) are rare congenital ectodermal dysplasias characterized by similar clinical features. To establish the genetic basis of AMS and BSS, we performed extensive clinical phenotyping, whole exome and candidate gene sequencing, and functional validations. We identified a recurrent de novo mutation in TWIST2 in seven independent AMS-affected families, as well as another recurrent de novo mutation affecting the same amino acid in ten independent BSS-affected families. Moreover, a genotype-phenotype correlation was observed, because the two syndromes differed based solely upon the nature of the substituting amino acid: a lysine at TWIST2 residue 75 resulted in AMS, whereas a glutamine or alanine yielded BSS. TWIST2 encodes a basic helix-loop-helix transcription factor that regulates the development of mesenchymal tissues. All identified mutations fell in the basic domain of TWIST2 and altered the DNA-binding pattern of Flag-TWIST2 in HeLa cells. Comparison of wild-type and mutant TWIST2 expressed in zebrafish identified abnormal developmental phenotypes and widespread transcriptome changes. Our results suggest that autosomal-dominant TWIST2 mutations cause AMS or BSS by inducing protean effects on the transcription factor's DNA binding.
Published: 2015

47. Comparison of human and rodent cell models to study myocardial lipid-induced insulin resistance

Author: Joost J. F. P. Luiken, Arthur van den Wijngaard, Shujin Wang, Miranda Nabben, Jan F. C. Glatz, Sabina J. V. Vanherle, Han G. Brunner, Ilvy M. E. Geraets, Li-Yen Wong, Moleculaire Genetica, RS: Carim - Heart, Genetica & Celbiologie, MUMC+: DA KG Lab Centraal Lab (9), MUMC+: DA Klinische Genetica (5), Klinische Genetica, and RS: Carim - H02 Cardiomyopathy
Subjects: 0301 basic medicine, medicine.medical_treatment, Induced Pluripotent Stem Cells, Clinical Biochemistry, Cell, CARDIAC MYOCYTES, Rodentia, 030209 endocrinology & metabolism, Diabetic cardiomyopathy, METABOLISM, Biology, CARDIOMYOCYTES, MECHANISMS, 03 medical and health sciences, 0302 clinical medicine, Insulin resistance, REDISTRIBUTION, medicine, Animals, Humans, Myocytes, Cardiac, FATTY-ACID UPTAKE, Induced pluripotent stem cell, Gene, 030109 nutrition & dietetics, Insulin, Fatty Acids, Cardiac function, Cell Differentiation, Transporter, Lipid overload, Cell Biology, medicine.disease, TRANSPORTERS, Embryonic stem cell, Cell biology, Cardiogenetics, Glucose, DIFFERENTIATION, medicine.anatomical_structure, CONTRACTILE DYSFUNCTION, Insulin Resistance, Cardiac metabolism, PLURIPOTENT STEM-CELLS
Abstract: Isolated or cultured cells have proven to be valuable model systems to investigate cellular (patho)biology and for screening of the efficacy of drugs or their possible side-effects. Pluripotent stem cells (PSC) can be readily obtained from healthy individuals as well as from diseased patients, and protocols have been developed to differentiate these cells into cardiomyocytes. Hence, these cellular models are moving center stage for a broader application. In this review, we focus on comparing mouse HL-1 cardiomyocytes, isolated adult rat cardiomyocytes, human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) for the study of metabolic aspects of cardiac functioning in health and disease. Various studies have reported that these cellular models are suitable for assessing substrate uptake and utilization, in that each display an adequate and similar response to physiological triggers, in particular the presence of insulin. Likewise, disease conditions, such as excess lipid supply, similarly affect each of these rodent and human cardiomyocyte models. It is concluded that PSC-CMs obtained from patients with cardiogenetic abnormalities are promising models to evaluate the functional consequence of gene variants with unknown significance.
Published: 2021

48. De Novo Mutations in SON Disrupt RNA Splicing of Genes Essential for Brain Development and Metabolism, Causing an Intellectual-Disability Syndrome

Author: Ssang-Taek Lim, Helger G. Yntema, Tara Funari, Alexander P.A. Stegmann, Daniel G. MacArthur, Jung-Hyun Kim, Bert B.A. de Vries, Alyson Krokosky, Joost Nicolai, Sha Tang, Serge Romana, Megan T. Cho, Joris A. Veltman, Berivan Baskin, Vandana Shashi, Clesson Turner, Deepali N. Shinde, Maja Hempel, Franco Laccone, Lisenka E.L.M. Vissers, Richard M. Myers, Grazia M.S. Mancini, Daniëlle G.M. Bosch, Eun-Young Erin Ahn, Tamison Jewett, Ganka Douglas, Margot R.F. Reijnders, Eun Young Park, Axel Neu, Dong-Er Zhang, Joshua K. Stone, Davor Lessel, Connie T.R.M. Stumpel, Helga Rehder, Christopher T. Gordon, Luis Rohena, Laurie B. Owen, Dima El-Khechen, Jana Behunova, Tim M. Strom, Julie Vogt, Andrea H. Seeley, Kirsty McWalter, Nuria C. Bramswig, Margje Sinnema, Marlène Rio, Natalie Hauser, Rebecca L. Belmonte, Servi J. C. Stevens, Kristin Lindstrom, Han G. Brunner, Fanny Kortüm, Kelly Schoch, Amber Begtrup, Kristine K. Bachman, Paula A. Bubulya, Stephanie L. Santoro, Jos M. T. Draaisma, Dagmar Wieczorek, Xu Yao, David L. Stachura, Slavé Petrovski, Gregory R. Wilson, David Traver, Clinical Genetics, Genetica & Celbiologie, MUMC+: DA KG Polikliniek (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, Klinische Genetica, Klinische Neurowetenschappen, MUMC+: MA Med Staf Spec Neurologie (9), MUMC+: DA KG Lab Centraal Lab (9), MUMC+: DA Pat Cytologie (9), and MUMC+: DA Klinische Genetica (5)
Subjects: 0301 basic medicine, Male, Developmental Disabilities, Medizin, Haploinsufficiency, Bioinformatics, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], 0302 clinical medicine, Intellectual disability, FLNA, Genetics(clinical), Eye Abnormalities, Zebrafish, Genetics (clinical), Genetics, Gene knockdown, Genes, Essential, biology, Brain, Syndrome, Disorders of movement Donders Center for Medical Neuroscience [Radboudumc 3], Pedigree, DNA-Binding Proteins, RNA splicing, Female, Heterozygote, RNA Splicing, Healthcare improvement science Radboud Institute for Health Sciences [Radboudumc 18], Minor Histocompatibility Antigens, 03 medical and health sciences, Metabolic Diseases, Intellectual Disability, Report, medicine, Animals, Humans, RNA, Messenger, Gene, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], RNA, medicine.disease, biology.organism_classification, Spine, 030104 developmental biology, Mutation, Head, 030217 neurology & neurosurgery
Abstract: Contains fulltext : 167701.pdf (Publisher’s version ) (Open Access) The overall understanding of the molecular etiologies of intellectual disability (ID) and developmental delay (DD) is increasing as next-generation sequencing technologies identify genetic variants in individuals with such disorders. However, detailed analyses conclusively confirming these variants, as well as the underlying molecular mechanisms explaining the diseases, are often lacking. Here, we report on an ID syndrome caused by de novo heterozygous loss-of-function (LoF) mutations in SON. The syndrome is characterized by ID and/or DD, malformations of the cerebral cortex, epilepsy, vision problems, musculoskeletal abnormalities, and congenital malformations. Knockdown of son in zebrafish resulted in severe malformation of the spine, brain, and eyes. Importantly, analyses of RNA from affected individuals revealed that genes critical for neuronal migration and cortex organization (TUBG1, FLNA, PNKP, WDR62, PSMD3, and HDAC6) and metabolism (PCK2, PFKL, IDH2, ACY1, and ADA) are significantly downregulated because of the accumulation of mis-spliced transcripts resulting from erroneous SON-mediated RNA splicing. Our data highlight SON as a master regulator governing neurodevelopment and demonstrate the importance of SON-mediated RNA splicing in human development.
Published: 2016

49. DNA Methylation Profiling of Uniparental Disomy Subjects Provides a Map of Parental Epigenetic Bias in the Human Genome

Author: Deborah J G Mackay, Paras Garg, Charles E. Schwartz, Stephen B. Montgomery, Giorgio Gimelli, Ricky S. Joshi, Claudia A. L. Ruivenkamp, Daniel Ho, Noah Zaitlen, Cédric Le Caignec, Thomas Eggermann, Urvashi Surti, Karin Buiting, Stylianos E. Antonarakis, Thomas H. Wassink, David O. Robinson, Thomas Liehr, Samuel G. Jacobson, Alistair T. Pagnamenta, Xin Li, Bernhard Steiner, Tuuli Lappalainen, Bradford Coffee, Andrew J. Sharp, David Francis, Peter Papenhausen, Han G. Brunner, Joep P.M. Geraedts, David A. Stevenson, Nidha Azam, Corey T. Watson, Sau Wai Cheung, and Nicole de Leeuw
Subjects: Male, Parents, 0301 basic medicine, Karyotype, Medizin, Biology, Article, Epigenesis, Genetic, Cohort Studies, Genomic Imprinting, 03 medical and health sciences, Intellectual Disability, Angelman syndrome, Genetics, medicine, Chromosomes, Human, Humans, Genetics(clinical), ddc:576.5, Epigenetics, Allele, Alleles, Genetics (clinical), Chromosome Aberrations, Chromosomes, Human, Pair 15, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Genome, Human, Sequence Analysis, RNA, Reproducibility of Results, DNA Methylation, Uniparental Disomy, medicine.disease, Uniparental disomy, 030104 developmental biology, Differentially methylated regions, CpG site, DNA methylation, CpG Islands, Female, Angelman Syndrome, Genomic imprinting, Microtubule-Associated Proteins, Prader-Willi Syndrome
Abstract: Contains fulltext : 167696.pdf (Publisher’s version ) (Open Access) Genomic imprinting is a mechanism in which gene expression varies depending on parental origin. Imprinting occurs through differential epigenetic marks on the two parental alleles, with most imprinted loci marked by the presence of differentially methylated regions (DMRs). To identify sites of parental epigenetic bias, here we have profiled DNA methylation patterns in a cohort of 57 individuals with uniparental disomy (UPD) for 19 different chromosomes, defining imprinted DMRs as sites where the maternal and paternal methylation levels diverge significantly from the biparental mean. Using this approach we identified 77 DMRs, including nearly all those described in previous studies, in addition to 34 DMRs not previously reported. These include a DMR at TUBGCP5 within the recurrent 15q11.2 microdeletion region, suggesting potential parent-of-origin effects associated with this genomic disorder. We also observed a modest parental bias in DNA methylation levels at every CpG analyzed across approximately 1.9 Mb of the 15q11-q13 Prader-Willi/Angelman syndrome region, demonstrating that the influence of imprinting is not limited to individual regulatory elements such as CpG islands, but can extend across entire chromosomal domains. Using RNA-seq data, we detected signatures consistent with imprinted expression associated with nine novel DMRs. Finally, using a population sample of 4,004 blood methylomes, we define patterns of epigenetic variation at DMRs, identifying rare individuals with global gain or loss of methylation across multiple imprinted loci. Our data provide a detailed map of parental epigenetic bias in the human genome, providing insights into potential parent-of-origin effects.
Published: 2016

50. Identification and functional characterization of de novo FOXP1 variants provides novel insights into the etiology of neurodevelopmental disorder

Author: Simon E. Fisher, Christian Gilissen, Henning Froehlich, Arianna Vino, Danai Dimitropoulou, Pelagia Deriziotis, Sarah A. Graham, Maaike Vreeburg, Elliot Sollis, Gudrun A. Rappold, Han G. Brunner, Rolph Pfundt, Genetica & Celbiologie, MUMC+: DA KG Polikliniek (9), MUMC+: DA Klinische Genetica (5), Klinische Genetica, and RS: GROW - R4 - Reproductive and Perinatal Medicine
Subjects: Neuroinformatics, Male, 0301 basic medicine, Adolescent, Transcription, Genetic, Developmental Disabilities, Molecular Sequence Data, Mutation, Missense, Biology, Frameshift mutation, 03 medical and health sciences, Neurodevelopmental disorder, Intellectual Disability, Genetics, medicine, Humans, Missense mutation, Exome, Language Development Disorders, Global developmental delay, Child, Molecular Biology, Genetics (clinical), Exome sequencing, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Base Sequence, Hypertelorism, High-Throughput Nucleotide Sequencing, Forkhead Transcription Factors, FOXP2, DNA, General Medicine, medicine.disease, Hypotonia, Pedigree, Repressor Proteins, 030104 developmental biology, Gene Expression Regulation, Female, medicine.symptom, Protein Binding, Signal Transduction
Abstract: Contains fulltext : 167384.pdf (Publisher’s version ) (Open Access) De novo disruptions of the neural transcription factor FOXP1 are a recently discovered, rare cause of sporadic intellectual disability (ID). We report three new cases of FOXP1-related disorder identified through clinical whole-exome sequencing. Detailed phenotypic assessment confirmed that global developmental delay, autistic features, speech/language deficits, hypotonia and mild dysmorphic features are core features of the disorder. We expand the phenotypic spectrum to include sensory integration disorder and hypertelorism. Notably, the etiological variants in these cases include two missense variants within the DNA-binding domain of FOXP1. Only one such variant has been reported previously. The third patient carries a stop-gain variant. We performed functional characterization of the three missense variants alongside our stop-gain and two previously described truncating/frameshift variants. All variants severely disrupted multiple aspects of protein function. Strikingly, the missense variants had similarly severe effects on protein function as the truncating/frameshift variants. Our findings indicate that a loss of transcriptional repression activity of FOXP1 underlies the neurodevelopmental phenotype in FOXP1-related disorder. Interestingly, the three novel variants retained the ability to interact with wild-type FOXP1, suggesting these variants could exert a dominant-negative effect by interfering with the normal FOXP1 protein. These variants also retained the ability to interact with FOXP2, a paralogous transcription factor disrupted in rare cases of speech and language disorder. Thus, speech/language deficits in these individuals might be worsened through deleterious effects on FOXP2 function. Our findings highlight that de novo FOXP1 variants are a cause of sporadic ID and emphasize the importance of this transcription factor in neurodevelopment.
Published: 2016

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