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98 results on '"Rami Abou Jamra"'

1. Prenatal phenotype of PNKP-related primary microcephaly associated with variants affecting both the FHA and phosphatase domain

Author

Tobias Bartolomaeus, Alejandro Leal, Katharina Schoner, Ilona Krey, Rami Abou Jamra, Luis Bermúdez-Guzmán, Steffen Syrbe, Helga Rehder, Susanna Schubert, Christian Roth, Sonja Neuser, Annemarie Schwan, Margit Plassmann, Maximilian Radtke, Diana Le Duc, Stefan Rohde, Bernt Popp, and Jan Henje Döring

Subjects
Adult, Male, Microcephaly, Genetic testing, RNA splicing, Mutation, Missense, Prenatal diagnosis, Biology, Compound heterozygosity, Article, Exon, Fetus, Neurodevelopmental disorder, Protein Domains, Prenatal Diagnosis, Genetics research, Genetics, medicine, Humans, Missense mutation, Genetics (clinical), medicine.disease, Paediatric neurological disorders, Micrencephaly, Phosphotransferases (Alcohol Group Acceptor), DNA Repair Enzymes, Phenotype, Female
Abstract

Biallelic PNKP variants cause heterogeneous disorders ranging from neurodevelopmental disorder with microcephaly/seizures to adult-onset Charcot–Marie–Tooth disease. To date, only postnatal descriptions exist. We present the first prenatal diagnosis of PNKP-related primary microcephaly. Pathological examination of a male fetus in the 18th gestational week revealed micrencephaly with extracerebral malformations and thus presumed syndromic microcephaly. A recessive disorder was suspected because of previous pregnancy termination for similar abnormalities. Prenatal trio-exome sequencing identified compound heterozygosity for the PNKP variants c.498G>A, p.[(=),0?] and c.302C>T, p.(Pro101Leu). Segregation confirmed both variants in the sister fetus. Through RNA analyses, we characterized exon 4 skipping affecting the PNKP forkhead-associated (FHA) and phosphatase domains (p.Leu67_Lys166del) as the predominant effect of the paternal c.498G>A variant. We retrospectively investigated two unrelated individuals diagnosed with biallelic PNKP-variants to compare prenatal/postnatal phenotypes. Both carry the splice donor variant c.1029+2T>C intrans with a variant in the FHA domain (c.311T>C, p.(Leu104Pro); c.151G>C, p.(Val51Leu)). RNA-seq showed complex splicing for c.1029+2T>C and c.151G>C. Structural modeling revealed significant clustering of missense variants in the FHA domain with variants generating structural damage. Our clinical description extends the PNKP-continuum to the prenatal stage. Investigating possible PNKP-variant effects using RNA and structural modeling, we highlight the mutational complexity and exemplify a PNKP-variant characterization framework.

Published
2021
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2. Heterozygous loss-of-function variants significantly expand the phenotypes associated with loss of GDF11

Author

Thomas A. Ravenscroft, Jennifer B. Phillips, Elizabeth Fieg, Sameer S. Bajikar, Judy Peirce, Jeremy Wegner, Alia A. Luna, Eric J. Fox, Yi-Lin Yan, Jill A. Rosenfeld, Jonathan Zirin, Oguz Kanca, Maria T. Acosta, Margaret Adam, David R. Adams, Pankaj B. Agrawal, Mercedes E. Alejandro, Justin Alvey, Laura Amendola, Ashley Andrews, Euan A. Ashley, Mahshid S. Azamian, Carlos A. Bacino, Guney Bademci, Eva Baker, Ashok Balasubramanya, Dustin Baldridge, Jim Bale, Michael Bamshad, Deborah Barbouth, Pinar Bayrak-Toydemir, Anita Beck, Alan H. Beggs, Edward Behrens, Gill Bejerano, Jimmy Bennet, Beverly Berg-Rood, Jonathan A. Bernstein, Gerard T. Berry, Anna Bican, Stephanie Bivona, Elizabeth Blue, John Bohnsack, Carsten Bonnenmann, Devon Bonner, Lorenzo Botto, Brenna Boyd, Lauren C. Briere, Elly Brokamp, Gabrielle Brown, Elizabeth A. Burke, Lindsay C. Burrage, Manish J. Butte, Peter Byers, William E. Byrd, John Carey, Olveen Carrasquillo, Ta Chen Peter Chang, Sirisak Chanprasert, Hsiao-Tuan Chao, Gary D. Clark, Terra R. Coakley, Laurel A. Cobban, Joy D. Cogan, Matthew Coggins, F. Sessions Cole, Heather A. Colley, Cynthia M. Cooper, Heidi Cope, William J. Craigen, Andrew B. Crouse, Michael Cunningham, Precilla D’Souza, Hongzheng Dai, Surendra Dasari, Joie Davis, Jyoti G. Dayal, Matthew Deardorff, Esteban C. Dell’Angelica, Shweta U. Dhar, Katrina Dipple, Daniel Doherty, Naghmeh Dorrani, Argenia L. Doss, Emilie D. Douine, David D. Draper, Laura Duncan, Dawn Earl, David J. Eckstein, Lisa T. Emrick, Christine M. Eng, Cecilia Esteves, Marni Falk, Liliana Fernandez, Carlos Ferreira, Elizabeth L. Fieg, Laurie C. Findley, Paul G. Fisher, Brent L. Fogel, Irman Forghani, Laure Fresard, William A. Gahl, Ian Glass, Bernadette Gochuico, Rena A. Godfrey, Katie Golden-Grant, Alica M. Goldman, Madison P. Goldrich, David B. Goldstein, Alana Grajewski, Catherine A. Groden, Irma Gutierrez, Sihoun Hahn, Rizwan Hamid, Neil A. Hanchard, Kelly Hassey, Nichole Hayes, Frances High, Anne Hing, Fuki M. Hisama, Ingrid A. Holm, Jason Hom, Martha Horike-Pyne, Alden Huang, Yong Huang, Laryssa Huryn, Rosario Isasi, Fariha Jamal, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Lefkothea Karaviti, Jennifer Kennedy, Dana Kiley, Isaac S. Kohane, Jennefer N. Kohler, Deborah Krakow, Donna M. Krasnewich, Elijah Kravets, Susan Korrick, Mary Koziura, Joel B. Krier, Seema R. Lalani, Byron Lam, Christina Lam, Grace L. LaMoure, Brendan C. Lanpher, Ian R. Lanza, Lea Latham, Kimberly LeBlanc, Brendan H. Lee, Hane Lee, Roy Levitt, Richard A. Lewis, Sharyn A. Lincoln, Pengfei Liu, Xue Zhong Liu, Nicola Longo, Sandra K. Loo, Joseph Loscalzo, Richard L. Maas, John MacDowall, Ellen F. Macnamara, Calum A. MacRae, Valerie V. Maduro, Marta M. Majcherska, Bryan C. Mak, May Christine V. Malicdan, Laura A. Mamounas, Teri A. Manolio, Rong Mao, Kenneth Maravilla, Thomas C. Markello, Ronit Marom, Gabor Marth, Beth A. Martin, Martin G. Martin, Julian A. Martínez-Agosto, Shruti Marwaha, Jacob McCauley, Allyn McConkie-Rosell, Colleen E. McCormack, Alexa T. McCray, Elisabeth McGee, Heather Mefford, J. Lawrence Merritt, Matthew Might, Ghayda Mirzaa, Eva Morava, Paolo Moretti, Paolo M. Moretti, Deborah Mosbrook-Davis, John J. Mulvihill, David R. Murdock, Anna Nagy, Mariko Nakano-Okuno, Avi Nath, Stan F. Nelson, John H. Newman, Sarah K. Nicholas, Deborah Nickerson, Shirley Nieves-Rodriguez, Donna Novacic, Devin Oglesbee, James P. Orengo, Laura Pace, Stephen Pak, J. Carl Pallais, Christina GS. Palmer, Jeanette C. Papp, Neil H. Parker, John A. Phillips, Jennifer E. Posey, Lorraine Potocki, Bradley Power, Barbara N. Pusey, Aaron Quinlan, Wendy Raskind, Archana N. Raja, Deepak A. Rao, Genecee Renteria, Chloe M. Reuter, Lynette Rives, Amy K. Robertson, Lance H. Rodan, Natalie Rosenwasser, Francis Rossignol, Maura Ruzhnikov, Ralph Sacco, Jacinda B. Sampson, Susan L. Samson, Mario Saporta, C. Ron Scott, Judy Schaechter, Timothy Schedl, Kelly Schoch, Daryl A. Scott, Vandana Shashi, Jimann Shin, Rebecca Signer, Edwin K. Silverman, Janet S. Sinsheimer, Kathy Sisco, Edward C. Smith, Kevin S. Smith, Emily Solem, Lilianna Solnica-Krezel, Ben Solomon, Rebecca C. Spillmann, Joan M. Stoler, Jennifer A. Sullivan, Kathleen Sullivan, Angela Sun, Shirley Sutton, David A. Sweetser, Virginia Sybert, Holly K. Tabor, Amelia L.M. Tan, Queenie K.-G. Tan, Mustafa Tekin, Fred Telischi, Willa Thorson, Audrey Thurm, Cynthia J. Tifft, Camilo Toro, Alyssa A. Tran, Brianna M. Tucker, Tiina K. Urv, Adeline Vanderver, Matt Velinder, Dave Viskochil, Tiphanie P. Vogel, Colleen E. Wahl, Stephanie Wallace, Nicole M. Walley, Chris A. Walsh, Melissa Walker, Jennifer Wambach, Jijun Wan, Lee-kai Wang, Michael F. Wangler, Patricia A. Ward, Daniel Wegner, Mark Wener, Tara Wenger, Katherine Wesseling Perry, Monte Westerfield, Matthew T. Wheeler, Jordan Whitlock, Lynne A. Wolfe, Jeremy D. Woods, Shinya Yamamoto, John Yang, Muhammad Yousef, Diane B. Zastrow, Wadih Zein, Chunli Zhao, Stephan Zuchner, Paul J. Benke, Eric S. Cameron, Vincent Strehlow, Konrad Platzer, Rami Abou Jamra, Chiara Klöckner, Matthew Osmond, Thomas Licata, Samantha Rojas, David Dyment, Josephine S.C. Chong, Sharyn Lincoln, John H. Postlethwait, Joel Krier, and Hugo J. Bellen

Subjects
0301 basic medicine, Craniofacial abnormality, Mutation, Missense, 030105 genetics & heredity, Biology, Article, Frameshift mutation, Craniofacial Abnormalities, 03 medical and health sciences, medicine, Animals, Humans, Missense mutation, Craniofacial, Allele, Zebrafish, Genetics (clinical), Loss function, Genetics, medicine.disease, biology.organism_classification, Phenotype, Spine, Growth Differentiation Factors, 030104 developmental biology, Bone Morphogenetic Proteins
Abstract

Purpose Growth differentiation factor 11 (GDF11) is a key signaling protein required for proper development of many organ systems. Only one prior study has associated an inherited GDF11 variant with a dominant human disease in a family with variable craniofacial and vertebral abnormalities. Here, we expand the phenotypic spectrum associated with GDF11 variants and document the nature of the variants. Methods We present a cohort of six probands with de novo and inherited nonsense/frameshift (4/6 patients) and missense (2/6) variants in GDF11. We generated gdf11 mutant zebrafish to model loss of gdf11 phenotypes and used an overexpression screen in Drosophila to test variant functionality. Results Patients with variants in GDF11 presented with craniofacial (5/6) , vertebral (5/6), neurological (6/6), visual (4/6), cardiac (3/6), auditory (3/6) and connective tissue abnormalities (3/6). gdf11 mutant zebrafish show craniofacial abnormalities and body segmentation defects that match some patient phenotypes. Expression of the patients’ variants in the fly showed that one nonsense variant in GDF11 is a severe loss-of-function (LOF) alleles whereas the missense variants in our cohort are partial LOF variants. Conclusion GDF11 is needed for human development, particularly neuronal development, and LOF GDF11 alleles can affect the development of numerous organs and tissues.

Published
2021
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3. The genetic landscape of intellectual disability and epilepsy in adults and the elderly: a systematic genetic work-up of 150 individuals

Author

Johannes Rebstock, Bernt Popp, Anne-Christin Teichmann, Malgorzata Kalita, Johannes R. Lemke, Tobias Bartolomaeus, Chiara Klöckner, Ilona Krey, Konrad Platzer, Mathias Stiller, Martin Finzel, Gudrun Körber, Susanne Horn, Frank Brandhoff, Pia Zacher, Thomas Mayer, Rami Abou Jamra, Julia Hentschel, Anja Heinze, Diana Le Duc, and Marina Nastainczyk-Wulf

Subjects
Adult, 0301 basic medicine, Pediatrics, medicine.medical_specialty, Article, Fragile X Mental Retardation Protein, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Intellectual Disability, Exome Sequencing, Intellectual disability, medicine, Humans, Medical diagnosis, Genetics (clinical), Exome sequencing, Aged, business.industry, medicine.disease, FMR1, Work-up, Fragile X syndrome, 030104 developmental biology, Neurodevelopmental Disorders, Karyotyping, Nuchal cord, business, 030217 neurology & neurosurgery
Abstract

Purpose Genetic diagnostics of neurodevelopmental disorders with epilepsy (NDDE) are predominantly applied in children, thus limited information is available regarding adults or elderly. Methods We investigated 150 adult/elderly individuals with NDDE by conventional karyotyping, FMR1 testing, chromosomal microarray, panel sequencing, and for unresolved cases, also by exome sequencing (nsingle = 71, ntrios = 24). Results We identified (likely) pathogenic variants in 71 cases (47.3%) comprising fragile X syndrome (n = 1), disease-causing copy number (n = 23), and single-nucleotide variants (n = 49). Seven individuals displayed multiple independent genetic diagnoses. The diagnostic yield correlated with the severity of intellectual disability. Individuals with anecdotal evidence of exogenic early-life events (e.g., nuchal cord, complications at delivery) with alleged/unproven association to the disorder had a particularly high yield of 58.3%. Screening for disease-specific comorbidities was indicated in 45.1% and direct treatment consequences arose in 11.8% of diagnosed individuals. Conclusion Panel/exome sequencing displayed the highest yield and should be considered as first-tier diagnostics in NDDE. This high yield and the numerous indications for additional screening or treatment modifications arising from genetic diagnoses indicate a current medical undersupply of genetically undiagnosed adult/elderly individuals with NDDE. Moreover, knowledge of the course of elderly individuals will ultimately help in counseling newly diagnosed individuals with NDDE.

Published
2021
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4. PET/MRI Delivers Multimodal Brain Signature in Alzheimer’s Disease with De Novo PSEN1 Mutation

Author

Henryk Barthel, Gayane Aghakhanyan, Solveig Tiepolt, Cordula Scherlach, Karl-Titus Hoffmann, Maria Strauss, Rami Abou Jamra, Osama Sabri, Michael Rullmann, Joseph Classen, Dorothee Saur, Christopher M. Weise, Matthias L. Schroeter, and Ken Marek

Subjects
Amyloid, business.industry, Hippocampus, medicine.disease, White matter, Atrophy, medicine.anatomical_structure, Neurology, medicine, PSEN1, Dementia, Neurology (clinical), business, Florbetaben, Neuroscience, Default mode network
Abstract

Background: Little is known so far about the brain phenotype and the spatial interplay of different Alzheimer’s disease (AD) biomarkers with structural and functional brain connectivity in the early phase of autosomal-dominant AD (ADAD). Multimodal PET/MRI might be suitable to fill this gap. Material and Methods: We presented a 31-year-old male patient without a family history of dementia with progressive worsening of memory and motor function. Two separate sessions of 3T PET/MRI acquisitions were arranged with the ß-amyloid tracer [18F]Florbetaben and the secondgeneration tau tracer [18F]PI-2620. Simultaneously acquired MRI consisted of high-resolution 3D T1, diffusion-tensor imaging (DTI), and resting-state fMRI. PET/MRI data were compared with ten age-matched healthy controls. Results: Widespread β-amyloid depositions were found in cortical regions, and striatum (Thal stage III) along with tau pathology restricted to the mesial-temporal structures (Braak stage III/IV). Volumetric/shape analysis of subcortical structures revealed atrophy of the hippocampal-amygdala complex. In addition, cortical thinning was detected in the right middle temporal pole. Alterations of multiple DTI indices were noted in the major white matter fiber bundles, together with disruption of default mode and sensory-motor network functional connectivity. Molecular genetic analysis by next-generation sequencing revealed a heterozygote missense pathogenic variant of the PSEN1 (Met233Val). Conclusion: Multimodal PET/MR imaging is able to deliver, in a one-stop-shop approach, an array of molecular, structural and functional brain information in AD due to de novo pathogenic variant, which can be studied for spatial interplay and might provide a rationale for initiating anti- amyloid/tau therapeutic approaches.

Published
2021
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5. Congenital cervical spine malformation due to bi‐allelic <scp>RIPPLY2</scp> variants in spondylocostal dysostosis type 6

Author

Ellen Totten, Rami Abou Jamra, Maria J. Guillen Sacoto, Christian L. Roth, Meret Wegler, Frauke Hornemann, Jillene Kogan, and Eckehard Schumann

Subjects
Male, 0301 basic medicine, media_common.quotation_subject, Nonsense, Mutation, Missense, Klippel–Feil syndrome, Ribs, Spinal canal stenosis, Scoliosis, 030105 genetics & heredity, 03 medical and health sciences, Myelopathy, Spinal Stenosis, Exome Sequencing, Genetics, medicine, Humans, Spasticity, Child, Alleles, Genetics (clinical), media_common, business.industry, Infant, Newborn, Dysostoses, Infant, Anatomy, medicine.disease, Spondylocostal dysostosis, Repressor Proteins, 030104 developmental biology, Somites, Spinal Cord, Codon, Nonsense, Face, Cervical Vertebrae, Female, RNA Splice Sites, medicine.symptom, Hemivertebrae, business
Abstract

RIPPLY2 is an essential part of the formation of somite patterning during embryogenesis and in establishment of rostro-caudal polarity. Here, we describe three individuals from two families with compound-heterozygous variants in RIPPLY2 (NM_001009994.2): c.238A > T, p.(Arg80*) and c.240-4 T > G, p.(?), in two 15 and 20 year old sisters, and a homozygous nonsense variant, c.238A > T, p.(Arg80*), in an 8 year old boy. All patients had multiple vertebral body malformations in the cervical and thoracic region, small or absent rib involvement, myelopathies, and common clinical features of SCDO6 including scoliosis, mild facial asymmetry, spinal spasticity and hemivertebrae. The nonsense variant can be classified as likely pathogenic based on the ACMG criteria while the splice variants must be classified as a variant of unknown significance. With this report on two further families, we confirm RIPPLY2 as the gene for SCDO6 and broaden the phenotype by adding myelopathy with or without spinal canal stenosis and spinal spasticity to the symptom spectrum. This article is protected by copyright. All rights reserved.

Published
2021
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6. In cis TP53 and RAD51C pathogenic variants may predispose to sebaceous gland carcinomas

Author

Matthias Stiller, Konrad Platzer, Hendrik Bläker, Carolin Meier, Astrid Monecke, Elisabeth Jäger, Rami Abou Jamra, Diana Le Duc, Johannes R. Lemke, Julia Hentschel, Sonja Neuser, Aleksander Markovic, and Mirjana Ziemer

Subjects
Adult, Male, Sebaceous gland, Biology, Article, Germline, Cancer syndrome, 03 medical and health sciences, 0302 clinical medicine, Genetics research, Genetics, medicine, Humans, Genetic Predisposition to Disease, Sebaceous Gland Neoplasms, Cancer genetics, Genetics (clinical), 030304 developmental biology, Genetic testing, 0303 health sciences, medicine.diagnostic_test, Carcinoma, medicine.disease, Penetrance, DNA-Binding Proteins, Chromosome 17 (human), Phenotype, medicine.anatomical_structure, 030220 oncology & carcinogenesis, Mutation, Cancer research, RAD51C, Sebaceous gland carcinoma, Tumor Suppressor Protein p53
Abstract

Pathogenic variants inTP53have been classically thought to cause Li-Fraumeni syndrome (LFS), a cancer predisposition with high risks for various childhood- and adult-onset malignancies. However, increased genetic testing has lately revealed, that pathogenic variant carriers exhibit a broader range of phenotypes and that penetrance may be dependent both on variant type and modifiers. Using next generation sequencing and short tandem repeat analysis, we identified germline pathogenic variants inTP53andRAD51Clocated incison chromosome 17 in a 43-year-old male, who has developed a rare sebaceous gland carcinoma (SGC) but so far no tumors of the LFS spectrum. This course mirrors aTrp53-Rad51c-double-mutantcismouse-model, which similarly develops SGC, while the characteristicTrp53-associated tumor spectrum occurs with significantly lower frequency. Therefore, we propose that co-occurent pathogenic variants inRAD51CandTP53may predispose to SGC, reminiscent of Muir-Torre syndrome. Further, this report supports the diversity of clinical presentations associated with germlineTP53alterations, and thus, the proposed expansion of LFS to heritableTP53-related cancer syndrome.

Published
2020
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7. Neonatal developmental and epileptic encephalopathy due to autosomal recessive variants in SLC13A5 gene

Author

Tiziana Granata, Elena Freri, Nina Barišić, Paola Costa, Stefania Magri, Paola De Liso, Rami Abou Jamra, Barbara Castellotti, Luciana Musante, Trine Bjørg Hammer, Carla Marini, Gaetan Lesca, Federico Vigevano, Sara Matricardi, Tilman Polster, Cinzia Gellera, Rikke S. Møller, Dana Craiu, and Julie Oertel

Subjects
Male, 0301 basic medicine, Proband, Phenytoin, Pediatrics, medicine.medical_specialty, Adolescent, Developmental Disabilities, Genetic counseling, Status epilepticus, neonatal, Young Adult, 03 medical and health sciences, 0302 clinical medicine, tooth hypoplasia, medicine, Humans, Genetic Predisposition to Disease, Child, development, Brain Diseases, Epilepsy, Symporters, business.industry, Genetic Variation, Electroencephalography, autosomal recessive, SLC13A5 gene, Carbamazepine, medicine.disease, Hypodontia, epileptic encephalopathy, 030104 developmental biology, Neurology, Child, Preschool, Developmental Milestone, Female, Phenobarbital, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery, Follow-Up Studies, medicine.drug
Abstract

Objective: Autosomal recessive pathogenic variants of the SLC13A5 gene are associated with severe neonatal epilepsy, developmental delay, and tooth hypoplasia/hypodontia. We report on 14 additional patients and compare their phenotypic features to previously published patients to identify the clinical hallmarks of this disorder. Methods: We collected clinical features of 14 patients carrying biallelic variants in SLC13A5 and performed a PubMed search to identify previously published patients. Results: All patients presented clonic or tonic seizures in the first days of life, evolving into status epilepticus in 57%. Analysis of seizure frequency and developmental milestones divided into five epochs showed an evolutionary trajectory of both items. In the first 3 years of life, 72% of patients had weekly/monthly seizures, often triggered by fever; 14% were seizure-free. Between the ages of 3 and 12 years, 60% become seizure-free; in the following years, up to age 18 years, 57% were seizure-free. After the age of 18 years, all three patients reaching this age were seizure-free. Similarly, 86% of patients at onset presented mild to moderate developmental impairment and diffuse hypotonia. In late childhood, all had developmental delay that was severe in most. Benzodiazepines, phenobarbital, phenytoin, and carbamazepine were the most effective drugs. Eight probands carried heterozygous compound variants, and homozygous pathogenic variants occurred in six. Literature review identified 45 patients carrying SLC13A5 gene pathogenic variants whose clinical features overlapped with our cohort. A peculiar and distinguishing sign is the presence of tooth hypoplasia and/or hypodontia in most patients. Significance: Autosomal recessive pathogenic variants in SLC13A5 are associated with a distinct neonatal epileptic encephalopathy evolving into severe cognitive and motor impairment, yet with seizures that settle down in late childhood. Tooth hypoplasia or hypodontia remains the peculiar feature. The SLC13A5 gene should be screened in neonatal epileptic encephalopathies; its recessive inheritance has relevance for genetic counseling.

Published
2020
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9. Unique variants in CLCN3, encoding an endosomal anion/proton exchanger, underlie a spectrum of neurodevelopmental disorders

Author

Anna R. Duncan, Tatjana Bierhals, Michael Pusch, Pamela Hawley, Amy Kritzer, Dagmar Wieczorek, Emanuele Agolini, Causes Study, Antonio Novelli, Raúl Estévez, Thomas J. Jentsch, Patricia Ellen Grant, Konrad Platzer, Margarete Koch-Hogrebe, Héctor Gaitán-Peñas, Andrea Maiorana, Anne H. O’Donnell-Luria, Johannes Luppe, Klaus Schmitz-Abe, Giovanna Stefania Colafati, Elliott H. Sherr, Pankaj B. Agrawal, Zaheer Valivullah, Elaina M England, Cornelius F. Boerkoel, Alysia Kern Lovgren, Lorne A. Clarke, Grace E. VanNoy, Emanuela Argilli, Kimberly Seath, Sara Bertelli, Maja Hempel, Anna Lehman, Thilo Diel, Maya M. Polovitskaya, Jill A. Madden, Yvette van Ierland, Rami Abou Jamra, Juanita Neira-Fresneda, Paolo Alfieri, and Clinical Genetics

Subjects
Male, hippocampus, gain of function, Xenopus, Medical and Health Sciences, Ion Channels, acidification, Mice, 2.1 Biological and endogenous factors, Missense mutation, Global developmental delay, Aetiology, Agenesis of the corpus callosum, Child, Genetics (clinical), Pediatric, Genetics & Heredity, Genetics, Mice, Knockout, Neurodegeneration, Homozygote, Biological Sciences, pH sensitivity, Phenotype, Mental Health, intellectual disability, voltage gated chloride channel, Child, Preschool, Neurological, Female, Adolescent, Knockout, Intellectual and Developmental Disabilities (IDD), Biology, neurodevelopmental delay, Article, Frameshift mutation, CAUSES Study, SDG 3 - Good Health and Well-being, Chloride Channels, medicine, Animals, Humans, Preschool, Gene, Animal, Neurosciences, Infant, Newborn, Infant, Newborn, CLCN, medicine.disease, biology.organism_classification, Brain Disorders, Disease Models, Animal, Neurodevelopmental Disorders, Disease Models, Mutation
Abstract

The genetic causes of global developmental delay (GDD) and intellectual disability (ID) are diverse and include variants in numerous ion channels and transporters. Loss-of-function variants in all five endosomal/lysosomal members of the CLC family of Cl− channels and Cl−/H+ exchangers lead to pathology in mice, humans, or both. We have identified nine variants in CLCN3, the gene encoding CIC-3, in 11 individuals with GDD/ID and neurodevelopmental disorders of varying severity. In addition to a homozygous frameshift variant in two siblings, we identified eight different heterozygous de novo missense variants. All have GDD/ID, mood or behavioral disorders, and dysmorphic features; 9/11 have structural brain abnormalities; and 6/11 have seizures. The homozygous variants are predicted to cause loss of ClC-3 function, resulting in severe neurological disease similar to the phenotype observed in Clcn3−/− mice. Their MRIs show possible neurodegeneration with thin corpora callosa and decreased white matter volumes. Individuals with heterozygous variants had a range of neurodevelopmental anomalies including agenesis of the corpus callosum, pons hypoplasia, and increased gyral folding. To characterize the altered function of the exchanger, electrophysiological analyses were performed in Xenopus oocytes and mammalian cells. Two variants, p.Ile607Thr and p.Thr570Ile, had increased currents at negative cytoplasmic voltages and loss of inhibition by luminal acidic pH. In contrast, two other variants showed no significant difference in the current properties. Overall, our work establishes a role for CLCN3 in human neurodevelopment and shows that both homozygous loss of ClC-3 and heterozygous variants can lead to GDD/ID and neuroanatomical abnormalities.

Published
2021

10. High-throughput splicing assays identify missense and silent splice-disruptive POU1F1 variants underlying pituitary hormone deficiency

Author

Thierry Brue, Jacob O. Kitzman, Frédérique Albarel, Cathy Smith, Julian Martinez Mayer, Hironori Bando, Peter Gergics, Mariam Maksutova, Debora Braslavsky, Julia Hoppmann, Sebastián Alexis Vishnopolska, Rami Abou Jamra, Qianyi Ma, Ignacio Bergadá, Berenice B. Mendonca, Frederic Castinetti, Sally A. Camper, Qing Fang, Marilena Nakaguma, Alexander A. L. Jorge, María Inés Pérez Millán, Ivo J.P. Arnhold, Michael H. Guo, Ana Keselman, Anne Barlier, Luciani R. Carvalho, A. Bilge Ozel, Roland Pfaeffle, Sajini Jayakody, Denise Rockstroh-Lippold, Andrew Dauber, Jun Li, Alexandru Saveanu, Marcelo A. Martí, University of Michigan [Ann Arbor], University of Michigan System, Universidade de São Paulo = University of São Paulo (USP), University Hospital Leipzig, Universidad de Buenos Aires [Buenos Aires] (UBA), 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), Institut Marseille Maladies Rares (MarMaRa), Aix Marseille Université (AMU), Service d'endocrinologie, diabète, maladies métaboliques [Hôpital de la Conception - APHM], University of Luebeck, Hospital de Niños 'Ricardo Gutiérrez', Laboratoire de Biochimie et de Biologie Moléculaire [Hôpital de la Conception - APHM], Hôpital de la Conception [CHU - APHM] (LA CONCEPTION), Leipzig University, West Chester University of Pennsylvania (WCUPA), National Children's Hospital, National Institutes of Health (R01HD097096to SAC, R01GM129123 to JOK), the Japan Society for Promotion of Science (HB), Grant 2013/03236-5 from the São Paulo Research Foundation (FAPESP) (IJPA), a grant from Pfizer (RP), and the Argentinean National Agency of Scientific and Technical Promotion, PICT 2016-2913 and PICT 2017-0002 (MIPM), Universidade de São Paulo (USP), University of Leipzig Medical Center, and Gall, Valérie

Subjects
Adult, Male, Gene isoform, growth hormone deficiency, PIT-1, variants of uncertain significance, Adolescent, RNA Splicing, [SDV]Life Sciences [q-bio], Repressor, 030209 endocrinology & metabolism, [SDV.GEN] Life Sciences [q-bio]/Genetics, Biology, Article, Growth hormone deficiency, 03 medical and health sciences, alternative splicing, 0302 clinical medicine, multiplexed assays of variant effects, Genetics, medicine, Humans, Missense mutation, splice, transcriptional regulation, Child, massively parallel splicing assay, Genetics (clinical), Loss function, 030304 developmental biology, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, [SDV.MHEP] Life Sciences [q-bio]/Human health and pathology, Alternative splicing, medicine.disease, High-Throughput Screening Assays, Pedigree, [SDV] Life Sciences [q-bio], Pituitary Hormones, hypopituitarism, Child, Preschool, Mutation, RNA splicing, Transcription Factor Pit-1, General Economics, Econometrics and Finance, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology
Abstract

International audience; Pituitary hormone deficiency occurs in ∼1:4,000 live births. Approximately 3% of the cases are due to mutations in the alpha isoform of POU1F1, a pituitary-specific transcriptional activator. We found four separate heterozygous missense variants in unrelated individuals with hypopituitarism that were predicted to affect a minor isoform, POU1F1 beta, which can act as a transcriptional repressor. These variants retain repressor activity, but they shift splicing to favor the expression of the beta isoform, resulting in dominant-negative loss of function. Using a high-throughput splicing reporter assay, we tested 1,070 single-nucleotide variants in POU1F1. We identified 96 splice-disruptive variants, including 14 synonymous variants. In separate cohorts, we found two additional synonymous variants nominated by this screen that co-segregate with hypopituitarism. This study underlines the importance of evaluating the impact of variants on splicing and provides a catalog for interpretation of variants of unknown significance in POU1F1.

Published
2021
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11. Choline transporter-like 1 deficiency causes a new type of childhood-onset neurodegeneration

Author

Dirk Klee, Eva Kildall Hejbøl, Ljubo Markovic, Marica Bakovic, Mark A. Tarnopolsky, Lauren Brady, Vernon W. Dolinsky, Maria Kibaek, Annette Seibt, Prasoon Agarwal, Else Gade, Rami Abou Jamra, Henrik Daa Schrøder, Martin Jakob Larsen, Adrian Taylor, Peter L. Nagy, Dagmar Wieczorek, Felix Distelmaier, Christina Fagerberg, and Nicholas A. Rouse

Subjects
0301 basic medicine, medicine.medical_specialty, Endoplasmic reticulum, Neurodegeneration, Substantia nigra, Biology, medicine.disease, Choline transporter, 03 medical and health sciences, chemistry.chemical_compound, 030104 developmental biology, 0302 clinical medicine, Atrophy, Endocrinology, chemistry, Phosphatidylcholine, Internal medicine, medicine, Choline, Neurology (clinical), Choline transport, 030217 neurology & neurosurgery
Abstract

Cerebral choline metabolism is crucial for normal brain function, and its homoeostasis depends on carrier-mediated transport. Here, we report on four individuals from three families with neurodegenerative disease and homozygous frameshift mutations (Asp517Metfs*19, Ser126Metfs*8, and Lys90Metfs*18) in the SLC44A1 gene encoding choline transporter-like protein 1. Clinical features included progressive ataxia, tremor, cognitive decline, dysphagia, optic atrophy, dysarthria, as well as urinary and bowel incontinence. Brain MRI demonstrated cerebellar atrophy and leukoencephalopathy. Moreover, low signal intensity in globus pallidus with hyperintensive streaking and low signal intensity in substantia nigra were seen in two individuals. The Asp517Metfs*19 and Ser126Metfs*8 fibroblasts were structurally and functionally indistinguishable. The most prominent ultrastructural changes of the mutant fibroblasts were reduced presence of free ribosomes, the appearance of elongated endoplasmic reticulum and strikingly increased number of mitochondria and small vesicles. When chronically treated with choline, those characteristics disappeared and mutant ultrastructure resembled healthy control cells. Functional analysis revealed diminished choline transport yet the membrane phosphatidylcholine content remained unchanged. As part of the mechanism to preserve choline and phosphatidylcholine, choline transporter deficiency was implicated in impaired membrane homeostasis of other phospholipids. Choline treatments could restore the membrane lipids, repair cellular organelles and protect mutant cells from acute iron overload. In conclusion, we describe a novel childhood-onset neurometabolic disease caused by choline transporter deficiency with autosomal recessive inheritance.

Published
2019
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12. De novo and inherited variants in ZNF292 underlie a neurodevelopmental disorder with features of autism spectrum disorder

Author

Jonathan A. Bernstein, Leah J. Rowe, Kimberly Foss, Samin A. Sajan, Kun Xia, Juliane Hoyer, Anita E. Beck, Shayna Svihovec, Vincent Gatinois, Lance H. Rodan, Roksana Sasanfar, Christiane Zweier, Alban Ziegler, Sonal Mahida, Kristin G. Monaghan, Charlotte W. Ockeloen, André Reis, Milen Velinov, Janson White, Evan E. Eichler, Nasim Vasli, Jennifer Friedman, Constance Smith-Hicks, Gilles Morin, Rachel Westman, Sandra Yang, Joshua Scheck, Christian Thiel, John B. Vincent, Deborah A. Nickerson, Michelle E. Ernst, Jacqueline Harris, Natasha Zeid, Bernt Popp, Francesca Mattioli, Zehra Agha, Ellen van Binsbergen, Julian A. Martinez-Agosto, Karen W. Gripp, Gwenaël Le Guyader, Catherine Vincent-Delorme, Lori-Anne Schillaci, Jennefer N. Kohler, Kimberly A. Aldinger, Laurence J. Walsh, Jessica X. Chong, David Geneviève, Rami Abou Jamra, Amy Yang, Cigdem I. Akman, Sha Tang, Ricardo Harripaul, Rick Person, Marleen Simon, Hui Guo, Muhammad Ayub, Laura S. Farach, Patricia Blanchet, Austin Larson, Marie Vincent, Luis Rohena, Michael J. Bamshad, Raheel Qamar, Gregory M. Enns, Joshua Rotenberg, Katelyn Payne, William J. Sunderland, Anne C.-H. Tsai, Annika M. Dries, Michèle Mathieu-Dramard, Dominique Bonneau, Ghayda M. Mirzaa, Bénédicte Gérard, Elise Schaefer, Amélie Piton, Patricia G Wheeler, Division of Medical Genetics [Seattle], University of Washington [Seattle], Détoxication et réparation tissulaire, Université de Rennes (UR)-Institut National de la Santé et de la Recherche Médicale (INSERM), Les Hôpitaux Universitaires de Strasbourg (HUS), Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Center for Integrative Brain Research [Seattle, WA, USA], University of Washington [Seattle]-Seattle Children's Research Institute, Central South University [Changsha], Campbell Family Mental Health Research Institute, Centre for Addiction and Mental Health (CAMH), Center for Integrative Brain Research, Ambry Genetics [Aliso Viejo, CA, USA], China Agricultural University (CAU), Biologie Neurovasculaire et Mitochondriale Intégrée (BNMI), Université d'Angers (UA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre Hospitalier Universitaire d'Angers (CHU Angers), PRES Université Nantes Angers Le Mans (UNAM), Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Kennedy Krieger Institute [Baltimore], Institute of Human Genetics [Erlangen, Allemagne], Universität Leipzig, Yale University [New Haven], Oregon Health and Science University [Portland] (OHSU), McGovern Medical School [Houston, Texas], Indiana University - Purdue University Indianapolis (IUPUI), Indiana University System, Indiana University [South Bend], The University of Texas at San Antonio (UTSA), New York State Psychiatric Institute, Columbia University [New York], Service de génétique médicale, CHU Strasbourg-Hôpital de Hautepierre [Strasbourg], CHU Strasbourg, Cellules Souches, Plasticité Cellulaire, Médecine Régénératrice et Immunothérapies (IRMB), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Montpellier (UM), Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), University Medical Center [Utrecht], Stanford University School of Medicine [CA, USA], Memorial Hermann Heart and Vascular Institute [Houston, TX, USA], University of Central Florida [Orlando] (UCF), Department of Pediatrics [Univ California San Diego] (UC San Diego), School of Medicine [Univ California San Diego] (UC San Diego), University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC)-University of California [San Diego] (UC San Diego), University of California (UC)-University of California (UC), University of Colorado Anschutz [Aurora], Department of Chemistry and Biochemistry [Bern], University of Bern, Columbia University Irving Medical Center (CUIMC), Signal Processing Lab [Boise - Idaho], Boise State University, University Hospitals Case Medical Center (CLEVELAND - UHCMC), University Hospitals Case Medical Center, Hôpital Jeanne de Flandres, Université de Lille, Droit et Santé-Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), Department of Psychology [University North Carolina Wilmington], University of North Carolina [Wilmington] (UNC), University of North Carolina System (UNC)-University of North Carolina System (UNC), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Centre hospitalier universitaire de Poitiers (CHU Poitiers), Service d'hématologie et immunologie, Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Université Paris Diderot - Paris 7 (UPD7), Unité de génétique médicale et oncogénétique [CHU Amiens Picardie], CHU Amiens-Picardie, Institut d'histoire du temps présent (IHTP), Centre National de la Recherche Scientifique (CNRS), University of Massachusetts Medical School [Worcester] (UMASS), University of Massachusetts System (UMASS), Queen's University [Kingston, Canada], Department of Molecular Genetics [Toronto], University of Toronto, GeneDx [Gaithersburg, MD, USA], Department of Genome Sciences [Seattle] (GS), Department of Pediatrics [Stanford], Stanford Medicine, Stanford University-Stanford University, Stanford School of Medicine [Stanford], Stanford University, University of California (UC), COMSATS Institute of Information Technology [Islamabad] (CIIT), Boston Children's Hospital, University of California [Los Angeles] (UCLA), Radboud University Medical Center [Nijmegen], Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Psychiatry, Seattle University [Seattle], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Institut National de la Santé et de la Recherche Médicale (INSERM), Universität Leipzig [Leipzig], Université de Montpellier (UM)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), Department of Pediatrics [san Diego], UC San Diego School of Medicine, Université Paris Diderot - Paris 7 (UPD7)-AP-HP - Hôpital Bichat - Claude Bernard [Paris], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), and University of California

Subjects
0301 basic medicine, Proband, Male, Adolescent, Autism Spectrum Disorder, autism spectrum disorders, Nerve Tissue Proteins, Neuroimaging, 030105 genetics & heredity, Biology, Article, 03 medical and health sciences, Neurodevelopmental disorder, ZNF292, Intellectual disability, mental disorders, Exome Sequencing, medicine, Humans, Genetic Predisposition to Disease, Child, Genetics (clinical), Exome sequencing, Genetics, Zinc finger, next generation sequencing, Genetic heterogeneity, High-Throughput Nucleotide Sequencing, medicine.disease, Phenotype, 3. Good health, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Autism spectrum disorder, intellectual disability, Neurodevelopmental Disorders, Child, Preschool, next-generation sequencing, [SDV.NEU]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC], Female, Carrier Proteins, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]
Abstract

Contains fulltext : 218267.pdf (Publisher’s version ) (Closed access) PURPOSE: Intellectual disability (ID) and autism spectrum disorder (ASD) are genetically heterogeneous neurodevelopmental disorders. We sought to delineate the clinical, molecular, and neuroimaging spectrum of a novel neurodevelopmental disorder caused by variants in the zinc finger protein 292 gene (ZNF292). METHODS: We ascertained a cohort of 28 families with ID due to putatively pathogenic ZNF292 variants that were identified via targeted and exome sequencing. Available data were analyzed to characterize the canonical phenotype and examine genotype-phenotype relationships. RESULTS: Probands presented with ID as well as a spectrum of neurodevelopmental features including ASD, among others. All ZNF292 variants were de novo, except in one family with dominant inheritance. ZNF292 encodes a highly conserved zinc finger protein that acts as a transcription factor and is highly expressed in the developing human brain supporting its critical role in neurodevelopment. CONCLUSION: De novo and dominantly inherited variants in ZNF292 are associated with a range of neurodevelopmental features including ID and ASD. The clinical spectrum is broad, and most individuals present with mild to moderate ID with or without other syndromic features. Our results suggest that variants in ZNF292 are likely a recurrent cause of a neurodevelopmental disorder manifesting as ID with or without ASD.

Published
2019
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13. Loss of function of SVBP leads to autosomal recessive intellectual disability, microcephaly, ataxia, and hypotonia

Author

Steffen Uebe, Nael Nadif Kasri, Heinrich Sticht, André Reis, Hans van Bokhoven, Wei Ba, Bassam Al Halak, Zafar Iqbal, Hasan Tawamie, Rami Abou Jamra, and Sheikh Riazuddin

Subjects
Genetics, Microcephaly, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Ataxia, Muscular hypotonia, Biology, medicine.disease, Hypotonia, All institutes and research themes of the Radboud University Medical Center, Real-time polymerase chain reaction, Intellectual disability, medicine, medicine.symptom, Gene, Genetics (clinical), Loss function
Abstract

Identifying and characterizing novel causes of autosomal recessive intellectual disability based on systematic clinical and genetic evaluation, followed by functional experiments. Clinical examinations, genome-wide positional mapping, and sequencing were followed by quantitative polymerase chain reaction and western blot of the protein SVBP and its interaction partners. We then knocked down the gene in rat primary hippocampal neurons and evaluated the consequences on synapses. We identified a founder, homozygous stop-gain variant in SVBP (c.82C>T; p.[Gln28*]) in four affected individuals from two independent families with intellectual disability, microcephaly, ataxia, and muscular hypotonia. SVBP encodes a small chaperone protein that transports and stabilizes two angiogenesis regulators, VASH1 and VASH2. The altered protein is unstable and nonfunctional since transfected HeLa cells with mutant SVBP did not reveal evidence for immunoreactive SVBP protein fragments and cotransfection with VASH1 showed a severe reduction of VASH1 in medium and cell lysate. Knocking down Svbp in rat primary hippocampal neurons led to a significant decrease in the number of excitatory synapses. SVBP is not only involved in angiogenesis, but also has vital functions in the central nervous system. Biallelic loss-of-function variants in SVBP lead to intellectual disability.

Published
2019
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14. Pontocerebellar hypoplasia due to bi-allelic variants in MINPP1

Author

Henry Houlden, Mohammad Yahya Vahidi Mehrjardi, Timo Roser, Julia Hoefele, Mohammadreza Dehghani, Rami Abou Jamra, Reza Maroofian, Anja Heinze, Stefan D. Roosendaal, Dagmar Wieczorek, Frank Baas, Margarete Koch-Hogrebe, Farrah Rajabi, Heinrich Sticht, Erin Torti, Matias Wagner, Bart Appelhof, Graduate School, ANS - Amsterdam Neuroscience, Radiology and Nuclear Medicine, Human Genetics, and ARD - Amsterdam Reproduction and Development

Subjects
Male, Protein Folding, Nonsense-mediated decay, Pontocerebellar hypoplasia, Mutation, Missense, Article, Serine, 03 medical and health sciences, chemistry.chemical_compound, 0302 clinical medicine, Cerebellar Diseases, Aspartic acid, INPP5E, Genetics, medicine, Missense mutation, Humans, Inositol, Allele, Child, Genetics (clinical), Alleles, 030304 developmental biology, 0303 health sciences, Chemistry, Homozygote, Neurodevelopmental disorders, Infant, medicine.disease, Phosphoric Monoester Hydrolases, ddc, Codon, Nonsense, Child, Preschool, Mutation, Female, 030217 neurology & neurosurgery
Abstract

Pontocerebellar hypoplasia (PCH) describes a group of rare heterogeneous neurodegenerative diseases with prenatal onset. Here we describe eight children with PCH from four unrelated families harboring the homozygous MINPP1 (NM_004897.4) variants; c.75_94del, p.(Leu27Argfs*39), c.851 C > A, p.(Ala284Asp), c.1210 C > T, p.(Arg404*), and c.992 T > G, p.(Ile331Ser). The homozygous p.(Leu27Argfs*39) change is predicted to result in a complete absence of MINPP1. The p.(Arg404*) would likely lead to a nonsense mediated decay, or alternatively, a loss of several secondary structure elements impairing protein folding. The missense p.(Ala284Asp) affects a buried, hydrophobic residue within the globular domain. The introduction of aspartic acid is energetically highly unfavorable and therefore predicted to cause a significant reduction in protein stability. The missense p.(Ile331Ser) affects the tight hydrophobic interactions of the isoleucine by the disruption of the polar side chain of serine, destabilizing the structure of MINPP1. The overlap of the above-mentioned genotypes and phenotypes is highly improbable by chance. MINPP1 is the only enzyme that hydrolyses inositol phosphates in the endoplasmic reticulum lumen and several studies support its role in stress induced apoptosis. The pathomechanism explaining the disease mechanism remains unknown, however several others genes of the inositol phosphatase metabolism (e.g., INPP5K, FIG4, INPP5E, ITPR1) are correlated with phenotypes of neurodevelopmental disorders. Taken together, we present MINPP1 as a novel autosomal recessive pontocerebellar hypoplasia gene.

Published
2021

15. High-throughput splicing assays identify missense and silent splice-disruptivePOU1F1variants underlying pituitary hormone deficiency

Author

Jacob O. Kitzman, Frederic Castinetti, Andrew Dauber, Julia Hoppmann, Ana Keselman, I J P Arnhold, Luciani R. Carvalho, Alexandru Saveanu, Denise Rockstroh-Lippold, Rami Abou Jamra, Jun Li, Alexander A. L. Jorge, Anne Barlier, Qing Fang, Sebastián Alexis Vishnopolska, Cathy Smith, Debora Braslavsky, Ignacio Bergadá, A. Bilge Ozel, Hironori Bando, Thierry Brue, Sally A. Camper, Frédérique Albarel, Peter Gergics, Julian Martinez Mayer, Marilena Nakaguma, María Inés Pérez Millán, Qianyi Ma, Roland Pfaeffle, Marcelo A. Martí, Berenice B. Mendonca, Mariam Maksutova, and Michael H. Guo

Subjects
Genetics, Gene isoform, RNA splicing, medicine, Repressor, Missense mutation, splice, Hypopituitarism, Biology, medicine.disease, Gene, Loss function
Abstract

Pituitary hormone deficiency occurs in ∼1:4,000 live births. Approximately 3% of the cases are due to mutations in the alpha isoform of POU1F1, a pituitary-specific transcriptional activator. We found four separate heterozygous missense variants in unrelated hypopituitarism patients that were predicted to affect a minor isoform, POU1F1 beta, which can act as a transcriptional repressor. These variants retain repressor activity, but they shift splicing to favor the expression of the beta isoform, resulting in dominant negative loss of function. Using a high throughput splicing reporter assay, we tested 1,080 single nucleotide variants inPOU1F1. We identified 113 splice disruptive variants, including 23 synonymous variants. We evaluated separate cohorts of hypopituitarism patients and found two different synonymous splice disruptive variants that co-segregate with hypopituitarism. This study underlines the importance of evaluating the impact of variants on splicing and provides a catalog for interpretation of variants of unknown significance in thePOU1F1gene.

Published
2021
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16. Disruption of RFX family transcription factors causes autism, attention-deficit/hyperactivity disorder, intellectual disability, and dysregulated behavior

Author

Tomi L. Toler, Timothy W. Yu, William B. Dobyns, Marcia C. Willing, Karen W. Gripp, Rolph Pfundt, Muhammad Iqbal, Xiadong Wang, Lance H. Rodan, Ada Hamosh, Cynthia S. Gubbels, Janice Baker, Thatjana Gardeitchik, Jenny Lai, André Reis, Fleur Vansenne, Jennifer E. Posey, Paranchai Boonsawat, Mathilde Nizon, Sébastien Küry, Jill R. Murrell, Julian L. Ambrus, Yunhong Wu, Laura A. Baker, Aubrie Soucy, Severine Audebert-Bellanger, Ellen van Binsbergen, Thomas Courtin, Guiseppe Zampino, Caleb P. Bupp, Holly K. Harris, Alan H. Beggs, Giulia Pascolini, Catharina (Nienke) M.L. Volker-Touw, Bert B.A. de Vries, Casie A. Genetti, La Donna L. Immken, Paola Grammatico, Martin Jakob Larsen, Sylvia Redon, Kévin Uguen, Reza Asadollahi, Madeleine Fannemel, Catherine Buchanan, Boris Keren, George E. Tiller, Lilian L. Cohen, Tojo Nakayama, Laurence E. Walsh, Iqra Ghulam Rasool, Audrey Labalme, Koen L.I. van Gassen, Pankaj B. Agrawal, Boxun Zhao, Gaetan Lesca, Steffan Syrbe, Kimberly A. Aldinger, Emanuele Agolini, Maria Kibaek, Muhammad Yasir Zahoor, Peter D. Turnpenny, Antonio Novelli, Ines Brösse, Claude Férec, Jorune Balciuniene, Nikoleta Argyrou, Victoria Suslovitch, Alice Poisson, Anita Rauch, Katelyn Payne, Christina Fagerberg, Cyril Mignot, Christopher Gray, Anne Blomhoff, Carolyn D. Applegate, Cornelia Kraus, Rami Abou Jamra, Marleen Simon, Martin Broly, Cara M. Skraban, and Emily Fassi

Subjects
Adult, 0301 basic medicine, Autism Spectrum Disorder, Regulatory Factor X Transcription Factors, 030105 genetics & heredity, Biology, Article, FRX, autism, intellectual disability, 03 medical and health sciences, Intellectual Disability, Ciliogenesis, Intellectual disability, mental disorders, medicine, Humans, Attention deficit hyperactivity disorder, Autistic Disorder, Gene, Genetics (clinical), Genetics, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], medicine.disease, Phenotype, Renal disorders Radboud Institute for Molecular Life Sciences [Radboudumc 11], 030104 developmental biology, Attention Deficit Disorder with Hyperactivity, Autism spectrum disorder, Autism, RFX3, Transcription Factors
Abstract

Contains fulltext : 234024.pdf (Publisher’s version ) (Closed access) PURPOSE: We describe a novel neurobehavioral phenotype of autism spectrum disorder (ASD), intellectual disability, and/or attention-deficit/hyperactivity disorder (ADHD) associated with de novo or inherited deleterious variants in members of the RFX family of genes. RFX genes are evolutionarily conserved transcription factors that act as master regulators of central nervous system development and ciliogenesis. METHODS: We assembled a cohort of 38 individuals (from 33 unrelated families) with de novo variants in RFX3, RFX4, and RFX7. We describe their common clinical phenotypes and present bioinformatic analyses of expression patterns and downstream targets of these genes as they relate to other neurodevelopmental risk genes. RESULTS: These individuals share neurobehavioral features including ASD, intellectual disability, and/or ADHD; other frequent features include hypersensitivity to sensory stimuli and sleep problems. RFX3, RFX4, and RFX7 are strongly expressed in developing and adult human brain, and X-box binding motifs as well as RFX ChIP-seq peaks are enriched in the cis-regulatory regions of known ASD risk genes. CONCLUSION: These results establish a likely role of deleterious variation in RFX3, RFX4, and RFX7 in cases of monogenic intellectual disability, ADHD and ASD, and position these genes as potentially critical transcriptional regulators of neurobiological pathways associated with neurodevelopmental disease pathogenesis.

Published
2021
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17. QRICH1 variants in Ververi‐Brady syndrome—delineation of the genotypic and phenotypic spectrum

Author

Martin Zenker, Melanie Föhrenbach, Christiane Zweier, Triantafyllia Brozou, Bernt Popp, Petra Muschke, Silke Redler, Harald Surowy, Arndt Borkhardt, Jörg Schaper, Dagmar Wieczorek, Rami Abou Jamra, and Linda K. Rey

Subjects
Male, 0301 basic medicine, Adolescent, Genotype, Developmental Disabilities, Mutation, Missense, 030105 genetics & heredity, Short stature, Frameshift mutation, 03 medical and health sciences, Loss of Function Mutation, Intellectual Disability, Genetics, Humans, Medicine, Missense mutation, Exome, Genetic Predisposition to Disease, ddc:610, Child, Frameshift Mutation, Genetics (clinical), business.industry, medicine.disease, QRICH1, Pediatric cancer, DNA-Binding Proteins, Developmental disorder, Phenotype, 030104 developmental biology, Codon, Nonsense, Autism spectrum disorder, Child, Preschool, Speech delay, Female, medicine.symptom, business, Transcription Factors
Abstract

Ververi‐Brady syndrome (VBS, # 617982) is a rare developmental disorder, and loss‐of‐function variants in QRICH1 were implicated in its etiology. Furthermore, a recognizable phenotype was proposed comprising delayed speech, learning difficulties and dysmorphic signs. Here, we present four unrelated individuals with one known nonsense variant (c.1954C > T; p.[Arg652*]) and three novel de novo QRICH1 variants, respectively. These included two frameshift mutations (c.832_833del; p.(Ser278Leufs*25), c.1812_1813delTG; p.(Glu605Glyfs*25)) and interestingly one missense mutation (c.2207G > A; p.[Ser736Asn]), expanding the mutational spectrum. Enlargement of the cohort by these four individuals contributes to the delineation of the VBS phenotype and suggests expressive speech delay, moderate motor delay, learning difficulties/mild ID, mild microcephaly, short stature and notable social behavior deficits as clinical hallmarks. In addition, one patient presented with nephroblastoma. The possible involvement of QRICH1 in pediatric cancer assumes careful surveillance a key priority for outcome of these patients. Further research and enlargement of cohorts are warranted to learn about the genetic architecture and the phenotypic spectrum in more detail.

Published
2020

19. Phenotypic expansion of CACNA1C-associated disorders to include isolated neurological manifestations

Author

Lance H. Rodan, Rebecca C. Spillmann, Harley T. Kurata, Shawn M. Lamothe, Jasmine Maghera, Rami Abou Jamra, Anna Alkelai, Stylianos E. Antonarakis, Isis Atallah, Omer Bar-Yosef, Frédéric Bilan, Kathrine Bjorgo, Xavier Blanc, Patrick Van Bogaert, Yoav Bolkier, Lindsay C. Burrage, Björn U. Christ, Jorge L. Granadillo, Patricia Dickson, Kirsten A. Donald, Christèle Dubourg, Aviva Eliyahu, Lisa Emrick, Kendra Engleman, Michaela Veronika Gonfiantini, Jean-Marc Good, Judith Kalser, Chiara Kloeckner, Guus Lachmeijer, Marina Macchiaiolo, Francesco Nicita, Sylvie Odent, Emily O’Heir, Xilma Ortiz-Gonzalez, Marta Pacio-Miguez, María Palomares-Bralo, Loren Pena, Konrad Platzer, Mathieu Quinodoz, Emmanuelle Ranza, Jill A. Rosenfeld, Eliane Roulet-Perez, Avni Santani, Fernando Santos-Simarro, Ben Pode-Shakked, Cara Skraban, Rachel Slaugh, Andrea Superti-Furga, Isabelle Thiffault, Richard H. van Jaabrsveld, Marie Vincent, Hong-Gang Wang, Pia Zacher, Mercedes E. Alejandro, Mahshid S. Azamian, Carlos A. Bacino, Ashok Balasubramanyam, Hsiao-Tuan Chao, Gary D. Clark, William J. Craigen, Hongzheng Dai, Shweta U. Dhar, Lisa T. Emrick, Alica M. Goldman, Neil A. Hanchard, Fariha Jamal, Lefkothea Karaviti, Seema R. Lalani, Brendan H. Lee, Richard A. Lewis, Ronit Marom, Paolo M. Moretti, David R. Murdock, Sarah K. Nicholas, James P. Orengo, Jennifer E. Posey, Lorraine Potocki, Susan L. Samson, Daryl A. Scott, Alyssa A. Tran, Tiphanie P. Vogel, Michael F. Wangler, Shinya Yamamoto, Christine M. Eng, Pengfei Liu, Patricia A. Ward, Edward Behrens, Matthew Deardorff, Marni Falk, Kelly Hassey, Kathleen Sullivan, Adeline Vanderver, David B. Goldstein, Heidi Cope, Allyn McConkie-Rosell, Kelly Schoch, Vandana Shashi, Edward C. Smith, Jennifer A. Sullivan, Queenie K.-G. Tan, Nicole M. Walley, Pankaj B. Agrawal, Alan H. Beggs, Gerard T. Berry, Lauren C. Briere, Laurel A. Cobban, Matthew Coggins, Cynthia M. Cooper, Elizabeth L. Fieg, Frances High, Ingrid A. Holm, Susan Korrick, Joel B. Krier, Sharyn A. Lincoln, Joseph Loscalzo, Richard L. Maas, Calum A. MacRae, J. Carl Pallais, Deepak A. Rao, Edwin K. Silverman, Joan M. Stoler, David A. Sweetser, Melissa Walker, Chris A. Walsh, Cecilia Esteves, Emily G. Kelley, Isaac S. Kohane, Kimberly LeBlanc, Alexa T. McCray, Anna Nagy, Surendra Dasari, Brendan C. Lanpher, Ian R. Lanza, Eva Morava, Devin Oglesbee, Guney Bademci, Deborah Barbouth, Stephanie Bivona, Olveen Carrasquillo, Ta Chen Peter Chang, Irman Forghani, Alana Grajewski, Rosario Isasi, Byron Lam, Roy Levitt, Xue Zhong Liu, Jacob McCauley, Ralph Sacco, Mario Saporta, Judy Schaechter, Mustafa Tekin, Fred Telischi, Willa Thorson, Stephan Zuchner, Heather A. Colley, Jyoti G. Dayal, David J. Eckstein, Laurie C. Findley, Donna M. Krasnewich, Laura A. Mamounas, Teri A. Manolio, John J. Mulvihill, Grace L. LaMoure, Madison P. Goldrich, Tiina K. Urv, Argenia L. Doss, Maria T. Acosta, Carsten Bonnenmann, Precilla D’Souza, David D. Draper, Carlos Ferreira, Rena A. Godfrey, Catherine A. Groden, Ellen F. Macnamara, Valerie V. Maduro, Thomas C. Markello, Avi Nath, Donna Novacic, Barbara N. Pusey, Camilo Toro, Colleen E. Wahl, Eva Baker, Elizabeth A. Burke, David R. Adams, William A. Gahl, May Christine V. Malicdan, Cynthia J. Tifft, Lynne A. Wolfe, John Yang, Bradley Power, Bernadette Gochuico, Laryssa Huryn, Lea Latham, Joie Davis, Deborah Mosbrook-Davis, Francis Rossignol, null Ben Solomon, John MacDowall, Audrey Thurm, Wadih Zein, Muhammad Yousef, Margaret Adam, Laura Amendola, Michael Bamshad, Anita Beck, Jimmy Bennett, Beverly Berg-Rood, Elizabeth Blue, Brenna Boyd, Peter Byers, Sirisak Chanprasert, Michael Cunningham, Katrina Dipple, Daniel Doherty, Dawn Earl, Ian Glass, Katie Golden-Grant, Sihoun Hahn, Anne Hing, Fuki M. Hisama, Martha Horike-Pyne, Gail P. Jarvik, Jeffrey Jarvik, Suman Jayadev, Christina Lam, Kenneth Maravilla, Heather Mefford, J. Lawrence Merritt, Ghayda Mirzaa, Deborah Nickerson, Wendy Raskind, Natalie Rosenwasser, C. Ron Scott, Angela Sun, Virginia Sybert, Stephanie Wallace, Mark Wener, Tara Wenger, Euan A. Ashley, Gill Bejerano, Jonathan A. Bernstein, Devon Bonner, Terra R. Coakley, Liliana Fernandez, Paul G. Fisher, Laure Fresard, Jason Hom, Yong Huang, Jennefer N. Kohler, Elijah Kravets, Marta M. Majcherska, Beth A. Martin, Shruti Marwaha, Colleen E. McCormack, Archana N. Raja, Chloe M. Reuter, Maura Ruzhnikov, Jacinda B. Sampson, Kevin S. Smith, Shirley Sutton, Holly K. Tabor, Brianna M. Tucker, Matthew T. Wheeler, Diane B. Zastrow, Chunli Zhao, William E. Byrd, Andrew B. Crouse, Matthew Might, Mariko Nakano-Okuno, Jordan Whitlock, Gabrielle Brown, Manish J. Butte, Esteban C. Dell’Angelica, Naghmeh Dorrani, Emilie D. Douine, Brent L. Fogel, Irma Gutierrez, Alden Huang, Deborah Krakow, Hane Lee, Sandra K. Loo, Bryan C. Mak, Martin G. Martin, Julian A. Martínez-Agosto, Elisabeth McGee, Stanley F. Nelson, Shirley Nieves-Rodriguez, Christina G.S. Palmer, Jeanette C. Papp, Neil H. Parker, Genecee Renteria, Rebecca H. Signer, Janet S. Sinsheimer, Jijun Wan, Lee-kai Wang, Katherine Wesseling Perry, Jeremy D. Woods, Justin Alvey, Ashley Andrews, Jim Bale, John Bohnsack, Lorenzo Botto, John Carey, Laura Pace, Nicola Longo, Gabor Marth, Paolo Moretti, Aaron Quinlan, Matt Velinder, Dave Viskochil, Pinar Bayrak-Toydemir, Rong Mao, Monte Westerfield, Anna Bican, Elly Brokamp, Laura Duncan, Rizwan Hamid, Jennifer Kennedy, Mary Kozuira, John H. Newman, John A. PhillipsIII, Lynette Rives, Amy K. Robertson, Emily Solem, Joy D. Cogan, F. Sessions Cole, Nichole Hayes, Dana Kiley, Kathy Sisco, Jennifer Wambach, Daniel Wegner, Dustin Baldridge, Stephen Pak, Timothy Schedl, Jimann Shin, Lilianna Solnica-Krezel, Eric Rush, Geoffrey S. Pitt, Ping Yee Billie Au, Boston Children's Hospital, University of Alberta, Universität Leipzig [Leipzig], Geneva University Hospital (HUG), Tel Aviv University [Tel Aviv], Service Génétique Médicale [CHU Poitiers], Centre hospitalier universitaire de Poitiers (CHU Poitiers), Cibles moléculaires et thérapeutiques de la maladie d'Alzheimer (CIMoTHeMA), Université de Poitiers, Laboratoire Jacques-Louis Lions (LJLL (UMR_7598)), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université de Paris (UP), Baylor College of Medicine (BCM), Baylor University, Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), CHU Pontchaillou [Rennes], Institut de Génétique et Développement de Rennes (IGDR), 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), Istituti di Ricovero e Cura a Carattere Scientifico (IRCCS), Lausanne University Hospital, Centre de référence Maladies Rares CLAD-Ouest [Rennes], Broad Institute of MIT and Harvard (BROAD INSTITUTE), Harvard Medical School [Boston] (HMS)-Massachusetts Institute of Technology (MIT)-Massachusetts General Hospital [Boston], Children’s Hospital of Philadelphia (CHOP ), Hospital Universitario La Paz, unité de recherche de l'institut du thorax UMR1087 UMR6291 (ITX), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Centre hospitalier universitaire de Nantes (CHU Nantes), Duke University [Durham], University of Kansas Medical Center [Lawrence], University of Missouri System, Children's Mercy Hospital [Kansas City], Weill Cornell Medicine [New York], University of Calgary, Research reported in this paper was supported by the NIH Common Fund, through the Office of Strategic Coordination/Office of the NIH Director under award number(s) (U01HG007709 [Baylor College of Medicine] and U01HG007672 [Duke University to V.S.]). Additional funding for this project was under award number 1RO1HD090132-01A1 (Cornell University to G.P.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health. Additional funding was provided by a Canadian Institutes of Health Research Grant (MOP-97988 to H.T.K.), and a Rowland and Muriel Haryett Fellowship (University of Alberta, to S.M.L.) and a fellowship from the Ministry of Education and Research of the Community of Madrid to M.P.M. (B2017/BMD-3721), and microgrant from the Rare Disease Foundation (P.Y.B.A. and H.T.K.). Sequencing and analysis was supported by the National Human Genome Research Institute grants UM1 HG008900 and R01 HG009141. K.A.D., B.C., and E.O. were supported the National Institute of Mental Health U01 MH119689., Universität Leipzig, Columbia University Medical Center (CUMC), Columbia University [New York], Tel Aviv University (TAU), Sorbonne Université (SU)-Centre National de la Recherche Scientifique (CNRS)-Université Paris Cité (UPCité), 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 ), Unité de recherche de l'institut du thorax (ITX-lab), University of Kansas Medical Center [Kansas City, KS, USA], Weill Cornell Medicine [Cornell University], and Cornell University [New York]

Subjects
Ataxia, Calcium Channels, L-Type, Long QT syndrome, Timothy syndrome, Bioinformatics, Article, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Intellectual disability, medicine, Missense mutation, Humans, Autistic Disorder, Genetics (clinical), 030304 developmental biology, 0303 health sciences, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, medicine.disease, Hypotonia, Long QT Syndrome, Phenotype, Autism, Syndactyly, medicine.symptom, business, 030217 neurology & neurosurgery
Abstract

International audience; Purpose:CACNA1C encodes the alpha-1-subunit of a voltage-dependent L-type calcium channel expressed in human heart and brain. Heterozygous variants in CACNA1C have previously been reported in association with Timothy syndrome and long QT syndrome. Several case reports have suggested that CACNA1C variation may also be associated with a primarily neurological phenotype.Methods:We describe 25 individuals from 22 families with heterozygous variants in CACNA1C, who present with predominantly neurological manifestations.Results:Fourteen individuals have de novo, nontruncating variants and present variably with developmental delays, intellectual disability, autism, hypotonia, ataxia, and epilepsy. Functional studies of a subgroup of missense variants via patch clamp experiments demonstrated differential effects on channel function in vitro, including loss of function (p.Leu1408Val), neutral effect (p.Leu614Arg), and gain of function (p.Leu657Phe, p.Leu614Pro). The remaining 11 individuals from eight families have truncating variants in CACNA1C. The majority of these individuals have expressive language deficits, and half have autism.Conclusion:We expand the phenotype associated with CACNA1C variants to include neurodevelopmental abnormalities and epilepsy, in the absence of classic features of Timothy syndrome or long QT syndrome.

Published
2020
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20. Biallelic GRM7 variants cause epilepsy, microcephaly, and cerebral atrophy

Author

Jill V. Hunter, Jaya Punetha, Davut Pehlivan, James R. Lupski, Rami Abou Jamra, Serkan Erdin, Haowei Du, Eric Boerwinkle, Tadahiro Mitani, Dana Marafi, Jozef Hertecant, Mohammed Almannai, Shalini N. Jhangiani, Jennifer E. Posey, Ender Karaca, Zeynep Coban Akdemir, Yavuz Bayram, Richard A. Gibbs, Jaishen Rajah, Kandamurugu Manickam, Sedat Isikay, Ayman W. El-Hattab, Jawid M Fatih, Jill A. Rosenfeld, and HKÜ, Sağlık Bilimleri Enstitüsü, Fizyoterapi ve Rehabilitasyon Anabilim Dalı

Subjects
Male, 0301 basic medicine, Microcephaly, Adolescent, Neurosciences. Biological psychiatry. Neuropsychiatry, Neurotransmission, Receptors, Metabotropic Glutamate, Cohort Studies, Consanguinity, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, Neurotransmitter receptor, Exome Sequencing, Humans, Medicine, Child, RC346-429, Research Articles, Alleles, Cerebral atrophy, business.industry, General Neuroscience, Metabotropic glutamate receptor 7, Glutamate receptor, Infant, medicine.disease, Pedigree, Phenotype, 030104 developmental biology, Neurodevelopmental Disorders, Child, Preschool, Female, Neurology. Diseases of the nervous system, Neurology (clinical), Atrophy, business, Candidate Disease Gene, Neuroscience, 030217 neurology & neurosurgery, Research Article, RC321-571
Abstract

Objective: Defects in ion channels and neurotransmitter receptors are implicated in developmental and epileptic encephalopathy (DEE). Metabotropic glutamate receptor 7 (mGluR7), encoded by GRM7, is a presynaptic G-protein-coupled glutamate receptor critical for synaptic transmission. We previously proposed GRM7 as a candidate disease gene in two families with neurodevelopmental disorders (NDDs). One additional family has been published since. Here, we describe three additional families with GRM7 biallelic variants and deeply characterize the associated clinical neurological and electrophysiological phenotype and molecular data in 11 affected individuals from six unrelated families. Methods: Exome sequencing and family-based rare variant analyses on a cohort of 220 consanguineous families with NDDs revealed three families with GRM7 biallelic variants; three additional families were identified through literature search and collaboration with a clinical molecular laboratory. Results: We compared the observed clinical features and variants of 11 affected individuals from the six unrelated families. Identified novel deleterious variants included two homozygous missense variants (c.2671G>A:p.Glu891Lys and c.1973G>A:p.Arg685Gln) and one homozygous stop-gain variant (c.1975C>T:p.Arg659Ter). Developmental delay, neonatal- or infantile-onset epilepsy, and microcephaly were universal. Three individuals had hypothalamic–pituitary–axis dysfunction without pituitary structural abnormality. Neuroimaging showed cerebral atrophy and hypomyelination in a majority of cases. Two siblings demonstrated progressive loss of myelination by 2 years in both and an acquired microcephaly pattern in one. Five individuals died in early or late childhood. Conclusion: Detailed clinical characterization of 11 individuals from six unrelated families demonstrates that rare biallelic GRM7 pathogenic variants can cause DEEs, microcephaly, hypomyelination, and cerebral atrophy. © 2020 The Authors. Annals of Clinical and Translational Neurology published by Wiley Periodicals, Inc on behalf of American Neurological Association.

Published
2020

21. KDM5A mutations identified in autism spectrum disorder using forward genetics

Author

R. Curtis Rogers, Henry Houlden, Miao Tang, Priscilla Anderton, Jamie Russell, Aboulfazl Rad, Islam Oguz Tuncay, Barbara R. DuPont, Anna Lehman, Maria H. Chahrour, Anja Heinze, Xiaohong Li, Hessa S. Alsaif, Camerun Washington, Amanda Gerard, Rami Abou Jamra, Pia Zacher, Kiran J Kaur, Causes Study, Mohammad Reza Abbaszadegan, Nadine Nijem, Maha Faden, Reza Maroofian, Lauretta El Hayek, Ellen R. Elias, Bruce Beutler, Madeline Couse, Raymond J. Louie, Sara Ludwig, and Kazem Hassanpour

Subjects
0301 basic medicine, Mouse, vocalization, QH301-705.5, Science, Genomics, autism spectrum disorder, Biology, General Biochemistry, Genetics and Molecular Biology, Transcriptome, 03 medical and health sciences, 0302 clinical medicine, chromatin regulator, histone demethylase, mental disorders, medicine, Biology (General), Exome sequencing, Genetics, General Immunology and Microbiology, Genetic heterogeneity, Microarray analysis techniques, General Neuroscience, Genetics and Genomics, General Medicine, medicine.disease, Phenotype, Forward genetics, forward genetics, 030104 developmental biology, Autism spectrum disorder, Medicine, 030217 neurology & neurosurgery, Research Article, Human
Abstract

Autism spectrum disorder (ASD) is a constellation of neurodevelopmental disorders with high phenotypic and genetic heterogeneity, complicating the discovery of causative genes. Through a forward genetics approach selecting for defective vocalization in mice, we identified Kdm5a as a candidate ASD gene. To validate our discovery, we generated a Kdm5a knockout mouse model (Kdm5a-/-) and confirmed that inactivating Kdm5a disrupts vocalization. In addition, Kdm5a-/- mice displayed repetitive behaviors, sociability deficits, cognitive dysfunction, and abnormal dendritic morphogenesis. Loss of KDM5A also resulted in dysregulation of the hippocampal transcriptome. To determine if KDM5A mutations cause ASD in humans, we screened whole exome sequencing and microarray data from a clinical cohort. We identified pathogenic KDM5A variants in nine patients with ASD and lack of speech. Our findings illustrate the power and efficacy of forward genetics in identifying ASD genes and highlight the importance of KDM5A in normal brain development and function.

Published
2020

22. Clinical, neuroimaging, and molecular spectrum of TECPR2 ‐associated hereditary sensory and autonomic neuropathy with intellectual disability

Author

Henry Houlden, David A. Sweetser, Hesham Aldhalaan, Barry J. Byrne, Bruria Ben-Zeev, Gabriela M. Repetto, Bernt Popp, Yasemin Dincer, Karima Maher, Reza Maroofian, Omar Ismayl, Fowzan S. Alkuraya, Susanna Schubert, Wen-Hann Tan, Jens Meiler, Usha Kini, Parul Jayakar, Fatima Khan, Darius Ebrahimi-Fakhari, Stephanie Efthymiou, Gehad ElGhazali, Mais Hashem, Vijayalakshmi Salem Ramakumaran, Volker Mall, Robert J. Graham, Bat El Bar-Aluma, Maria Cecilia Poli, Rami Abou Jamra, Barbara Brechmann, Asma E. Al Nuaimi, Gali Heimer, Sonja Neuser, Amir Szeinberg, Ines Brösse, Christian Behrends, Angelika Seitz, Mandy Krumbiegel, Jennifer E. Posey, Amal Al Tenaiji, Lauren O’Grady, Michael Zech, Siddharth Srivastava, James R. Lupski, Basil T. Darras, Isabella Herman, Alistair T. Pagnamenta, Juliane Winkelmann, Shahnaz Ibrahim, Yael Haberman, and Tatiana Muñoz

Subjects
Male, Models, Molecular, Ataxia, Adolescent, Protein Conformation, Population, Mutation, Missense, Nerve Tissue Proteins, Neuroimaging, Disease, Biology, Bioinformatics, Cohort Studies, 03 medical and health sciences, Neurodevelopmental disorder, Intellectual Disability, Human Phenotype Ontology, Intellectual disability, Hereditary sensory and autonomic neuropathy, Genetics, medicine, Missense mutation, Humans, Family, Global developmental delay, Hereditary Sensory and Autonomic Neuropathies, education, Child, Genetics (clinical), 030304 developmental biology, education.field_of_study, 0303 health sciences, business.industry, 030305 genetics & heredity, Infant, Hyporeflexia, medicine.disease, Magnetic Resonance Imaging, Pedigree, ddc, Cross-Sectional Studies, Phenotype, Child, Preschool, Female, medicine.symptom, business, Carrier Proteins
Abstract

PURPOSEBi-allelic TECPR2 variants have been associated with a complex syndrome with features of both a neurodevelopmental and neurodegenerative disorder. Here, we provide a comprehensive clinical description and variant interpretation framework for this genetic locus.METHODSThrough an international collaboration, we identified 17 individuals from 15 families with bi-allelic TECPR2-variants. We systemically reviewed clinical and molecular data from this cohort and 11 cases previously reported. Phenotypes were standardized using Human Phenotype Ontology terms.RESULTSA cross-sectional analysis revealed global developmental delay/intellectual disability, muscular hypotonia, ataxia, hyporeflexia, respiratory infections and central/nocturnal hypopnea as core manifestations. A review of brain MRI scans demonstrated a thin corpus callosum in 52%. We evaluated 17 distinct variants. Missense variants in TECPR2 are predominantly located in the N- and C-terminal regions containing β-propeller repeats. Despite constituting nearly half of disease associated TECPR2 variants, classifying missense variants as (likely) pathogenic according to ACMG criteria remains challenging. We estimate a pathogenic variant carrier frequency of 1/1,221 in the general and 1/155 in the Jewish Ashkenazi populations.CONCLUSIONBased on clinical, neuroimaging and genetic data, we provide recommendations for variant reporting, clinical assessment, and surveillance/treatment of individuals with TECPR2-associated disorder. This sets the stage for future prospective natural history studies.CONFLICTS OF INTERESTAll authors involved in the study declare no conflicts of interest relevant to this study.

Published
2020

23. Author response: KDM5A mutations identified in autism spectrum disorder using forward genetics

Author

Priscilla Anderton, Miao Tang, Aboulfazl Rad, Barbara R. DuPont, Xiaohong Li, Bruce Beutler, Kiran J Kaur, Madeline Couse, Islam Oguz Tuncay, R. Curtis Rogers, Henry Houlden, Pia Zacher, Rami Abou Jamra, Anja Heinze, Camerun Washington, Maha Faden, Nadine Nijem, Mohammad Reza Abbaszadegan, Kazem Hassanpour, Reza Maroofian, Amanda Gerard, Hessa S. Alsaif, Lauretta El Hayek, Sara Ludwig, Anna Lehman, Maria H. Chahrour, Jamie Russell, Causes Study, Ellen R. Elias, and Raymond J. Louie

Subjects
Genetics, Autism spectrum disorder, medicine, Psychology, medicine.disease, Forward genetics
Published
2020
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24. Hemiplegic Migraine in Glut1 Deficiency Syndrome and Paroxysmal Dyskinesia at Ketogenic Diet Induction: Case Report and Literature Review

Author

Anja Heinze, Andreas Merkenschlager, Rami Abou Jamra, and Janina Gburek-Augustat

Subjects
0301 basic medicine, Pediatrics, medicine.medical_specialty, endocrine system, Deficiency syndrome, Paroxysmal nonkinesigenic dyskinesia, medicine.medical_treatment, Central nervous system, 030105 genetics & heredity, 03 medical and health sciences, 0302 clinical medicine, medicine, Case Series with Literature Review, business.industry, nutritional and metabolic diseases, Paroxysmal dyskinesia, medicine.disease, Discontinuation, carbohydrates (lipids), medicine.anatomical_structure, Neurology, Hemiplegic migraine, Neurology (clinical), Complication, business, 030217 neurology & neurosurgery, hormones, hormone substitutes, and hormone antagonists, Ketogenic diet
Abstract

Background A rare symptom of Glut1 deficiency syndrome (Glut1 DS) is hemiplegic migraine (HM). Case We report a patient with Glut1 DS with a mild phenotype. His leading symptom was HM. As an unusual complication of the initiation of a ketogenic diet (KD), our patient developed paroxysmal nonkinesigenic dyskinesia. Paroxysmal dyskinesia occurred first and exclusively at the initiation of KD. Literature review There are a few case reports for HM in Glut1 DS. All patients had additional neurological symptoms. Regarding central nervous system symptoms such as paroxysmal dyskinesia triggered by KD, we found only 1 other case report. Discussion HM is part of the symptom complex of Glut1 DS and can be effectively treated by KD. Paroxysmal dyskinesia trigged by the initiation of KD should not lead to the discontinuation of the diet in Glut1 DS.

Published
2020

25. Novel congenital disorder of O-linked glycosylation caused by GALNT2 loss of function

Author

Elena Gardella, Damir Musaev, Cecilia Vitali, Emanuele Agolini, Sumeet A. Khetarpal, Kimiyo Raymond, Daniel J. Rader, Camilla Gøbel Madsen, Valentina Stanley, Antonio Novelli, Andrew C. Edmondson, W. Timothy O'Brien, Heiko Reutter, John Hintze, Kristen Liedtke, Mahmoud Y. Issa, Lars Hansen, Christina Fenger, Kevin Rostasy, Rami Abou Jamra, Maha S. Zaki, Francesca Romana Lepri, Ulla E. Petäjä-Repo, Joseph G. Gleeson, Rikke S. Møller, Silvana Briuglia, Katrine T. Schjoldager, Lorenzo Sinibaldi, Viola Alesi, Guido Rubboli, Raffaella Cusmai, and Monica Zilmer

Subjects
0301 basic medicine, Male, medicine.medical_specialty, Glycosylation, Adolescent, Congenital disorders of glycosylation, O-glycosylation, GALNT2, Apolipoprotein C-III glycosylation, HDL-cholesterol, Developmental Disabilities, Biology, 03 medical and health sciences, chemistry.chemical_compound, Mice, Young Adult, 0302 clinical medicine, Loss of Function Mutation, Internal medicine, medicine, Animals, Humans, Congenital disorders of glycosylation, Global developmental delay, Child, O-glycosylation, Apolipoprotein C-III, Original Articles, medicine.disease, HDL-cholesterol, Pedigree, Rats, Developmental disorder, 030104 developmental biology, Endocrinology, chemistry, GALNT2, Child, Preschool, O-linked glycosylation, Apolipoprotein C-III glycosylation, N-Acetylgalactosaminyltransferases, Apolipoprotein C3, lipids (amino acids, peptides, and proteins), Female, Neurology (clinical), Congenital disorder of glycosylation, Lipid glycosylation, 030217 neurology & neurosurgery, Congenital disorder
Abstract

Congenital disorders of glycosylation are a growing group of rare genetic disorders caused by deficient protein and lipid glycosylation. Here, we report the clinical, biochemical, and molecular features of seven patients from four families with GALNT2-congenital disorder of glycosylation (GALNT2-CDG), an O-linked glycosylation disorder. GALNT2 encodes the Golgi-localized polypeptide N-acetyl-d-galactosamine-transferase 2 isoenzyme. GALNT2 is widely expressed in most cell types and directs initiation of mucin-type protein O-glycosylation. All patients showed loss of O-glycosylation of apolipoprotein C-III, a non-redundant substrate for GALNT2. Patients with GALNT2-CDG generally exhibit a syndrome characterized by global developmental delay, intellectual disability with language deficit, autistic features, behavioural abnormalities, epilepsy, chronic insomnia, white matter changes on brain MRI, dysmorphic features, decreased stature, and decreased high density lipoprotein cholesterol levels. Rodent (mouse and rat) models of GALNT2-CDG recapitulated much of the human phenotype, including poor growth and neurodevelopmental abnormalities. In behavioural studies, GALNT2-CDG mice demonstrated cerebellar motor deficits, decreased sociability, and impaired sensory integration and processing. The multisystem nature of phenotypes in patients and rodent models of GALNT2-CDG suggest that there are multiple non-redundant protein substrates of GALNT2 in various tissues, including brain, which are critical to normal growth and development.

Published
2020
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26. De novo mutations in the X-linked TFE3 gene cause intellectual disability with pigmentary mosaicism and storage disorder-like features

Author

Bertrand Isidor, Rami Abou Jamra, Virginie Carmignac, Yannis Duffourd, Helio Pedro, Eriko Koshimizu, Maja Hempel, Tobias Bartolomaeus, Martin Chevarin, Floor A. M. Duijkers, Maria J. Guillen Sacoto, Erin Torti, David Geneviève, David J. Harris, Valerie Loik Ramey, Klaske D. Lichtenbelt, Arthur Sorlin, Miriam Maik, Anne Guimier, Paul Kuentz, Tatjana Bierhals, Orly Elpeleg, Yoshiko Murakami, Laurence Faivre, Jean Baptiste Rivière, Jill Clayton-Smith, Laurent Pasquier, Yuichi Abe, Edgard Verdura, Aviva Fattal, Judith St-Onge, Daphné Lehalle, Joerg Betschinger, Krista Sondergaard-Schatz, Laurie Simone, Christa W. Habela, Ivon Cusco, Mieke M. van Haelst, Pierre Vabres, Laurence Duplomb, Magali Avila, Sakoto Miyakate, Koen L.I. van Gassen, Julien Thevenon, Eveline S. J. M. de Bont, Benjamin Cogné, Pia Zacher, Silvana van Koningsbruggen, Thibaud Jouan, Irene Valenzuela, Christel Thauvin-Robinet, Salvy-Córdoba, Nathalie, FHU TRANSLAD (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), Service de Génétique médicale [CHU Pitié-Salpêtrière], CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Universitaetsklinikum Hamburg-Eppendorf = University Medical Center Hamburg-Eppendorf [Hamburg] (UKE), GeneDx [Gaithersburg, MD, USA], National Center for Child Health and Development [Tokyo], University Hospital Leipzig, Manchester Centre for Genomic Medicine [Manchester, UK] (MCGM), St Mary's Hospital Manchester-Manchester Academic Health Science Centre (MAHSC), University of Manchester [Manchester]-University of Manchester [Manchester]-Manchester University NHS Foundation Trust (MFT)-Faculty of Biology, Medicine and Health [Manchester, UK], University of Manchester [Manchester], Centre hospitalier universitaire de Nantes (CHU Nantes), Unité de recherche de l'institut du thorax (ITX-lab), Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS)-Université de Nantes - UFR de Médecine et des Techniques Médicales (UFR MEDECINE), Université de Nantes (UN)-Université de Nantes (UN), Vall d'Hebron University Hospital [Barcelona], University Medical Center Groningen [Groningen] (UMCG), VU University Medical Center [Amsterdam], Department of Genetics and Metabolic Diseases and the Monique and Jacques Roboh Department of Genetic Research, Hadassah Hebrew University Medical Center [Jerusalem], Tel Aviv Sourasky Medical Center [Te Aviv], Département de génétique médicale, maladies rares et médecine personnalisée [CHRU Montpellier], Centre Hospitalier Régional Universitaire [Montpellier] (CHRU Montpellier), CHU Necker - Enfants Malades [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP), Boston Children's Hospital, Centre Hospitalier Régional Universitaire de Besançon (CHRU Besançon), Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Brain Centre Rudolf Magnus [Utrecht], University Medical Center [Utrecht], Hackensack University Medical Center [Hackensack], Yokohama City University (YCU), Osaka University [Osaka], CHU Pontchaillou [Rennes], Johns Hopkins University School of Medicine [Baltimore], Child Health and Human Development Program [Montréal, QC, Canada], McGill University Health Center [Montreal] (MUHC), Centre Hospitalier Universitaire [Grenoble] (CHU), University Hospital Erlangen = Uniklinikum Erlangen, Department of Clinical Genetics, Academic Medical Centre, Amsterdam, Institut d'Investigació Biomèdica de Bellvitge [Barcelone] (IDIBELL), CIBER de Enfermedades Raras (CIBERER), Kleinwachau - Saxon Epilepsy Center Radeberg, Department of Human Genetics [Montréal], McGill University = Université McGill [Montréal, Canada], Friedrich Miescher Institute for Biomedical Research (FMI), Novartis Research Foundation, Human Genetics, ACS - Pulmonary hypertension & thrombosis, ARD - Amsterdam Reproduction and Development, Human genetics, Amsterdam Neuroscience - Complex Trait Genetics, and Amsterdam Reproduction & Development (AR&D)

Subjects
0301 basic medicine, MESH: Basic Helix-Loop-Helix Leucine Zipper Transcription Factors, [SDV.NEU.NB]Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, Intellectual disability, TFE3, Biology, [SDV.GEN.GH] Life Sciences [q-bio]/Genetics/Human genetics, MESH: Intellectual Disability, 03 medical and health sciences, Exon, 0302 clinical medicine, MESH: Whole Exome Sequencing, MESH: Child, Genetics, medicine, Missense mutation, Gene, Genetics (clinical), Exome sequencing, Pigmentary mosaicism, MESH: Pathology, Molecular, MESH: Adolescent, MESH: Humans, Alternative splicing, Lysosomal metabolism, MESH: Child, Preschool, [SDV.NEU.NB] Life Sciences [q-bio]/Neurons and Cognition [q-bio.NC]/Neurobiology, MESH: Adult, medicine.disease, Phenotype, MESH: Infant, MESH: Male, Storage disorder, 030104 developmental biology, MESH: Genes, X-Linked, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, MESH: Young Adult, MESH: Epilepsy, MESH: Mosaicism, MESH: Pigmentation Disorders, MESH: Female, 030217 neurology & neurosurgery
Abstract

IntroductionPigmentary mosaicism (PM) manifests by pigmentation anomalies along Blaschko’s lines and represents a clue toward the molecular diagnosis of syndromic intellectual disability (ID). Together with new insights on the role for lysosomal signalling in embryonic stem cell differentiation, mutations in the X-linked transcription factor 3 (TFE3) have recently been reported in five patients. Functional analysis suggested these mutations to result in ectopic nuclear gain of functions.Materials and methodsSubsequent data sharing allowed the clustering of de novo TFE3 variants identified by exome sequencing on DNA extracted from leucocytes in patients referred for syndromic ID with or without PM.ResultsWe describe the detailed clinical and molecular data of 17 individuals harbouring a de novo TFE3 variant, including the patients that initially allowed reporting TFE3 as a new disease-causing gene. The 12 females and 5 males presented with pigmentation anomalies on Blaschko’s lines, severe ID, epilepsy, storage disorder-like features, growth retardation and recognisable facial dysmorphism. The variant was at a mosaic state in at least two male patients. All variants were missense except one splice variant. Eleven of the 13 variants were localised in exon 4, 2 in exon 3, and 3 were recurrent variants.ConclusionThis series further delineates the specific storage disorder-like phenotype with PM ascribed to de novo TFE3 mutation in exons 3 and 4. It confirms the identification of a novel X-linked human condition associated with mosaicism and dysregulation within the mechanistic target of rapamycin (mTOR) pathway, as well as a link between lysosomal signalling and human development.

Published
2020
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27. Variants in PUS7 Cause Intellectual Disability with Speech Delay, Microcephaly, Short Stature, and Aggressive Behavior

Author

F. Lucy Raymond, Lonneke de Boer, Michal Minczuk, Rami Abou Jamra, Nadja Dinges, Modi Safra, Zubair M. Ahmed, Detilina Grozeva, Hans van Bokhoven, Pedro Rebelo-Guiomar, Mohsin Shahzad, Clara Soyris, Violeta Morin, Mureed Hussain, Nadine Körtel, Michael Stock, Saima Riazuddin, Daniel L. Polla, Jean-Yves Roignant, Arjan P.M. de Brouwer, Avia Zisso, André Reis, Schraga Schwartz, Christopher A. Powell, David A. Koolen, Sheikh Riazuddin, Rolph Pfundt, and Franziska Schwarz

Subjects
Male, 0301 basic medicine, Microcephaly, Adolescent, Poison control, Dwarfism, Biology, Short stature, Gene Knockout Techniques, 03 medical and health sciences, Exon, All institutes and research themes of the Radboud University Medical Center, RNA, Transfer, Intellectual Disability, Report, Intellectual disability, Genetics, medicine, Animals, Humans, Language Development Disorders, RNA, Messenger, Child, Genetics (clinical), Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Homozygote, Genetic Variation, RNA, Metabolic Disorders Radboud Institute for Molecular Life Sciences [Radboudumc 6], Exons, medicine.disease, Pedigree, Aggression, Drosophila melanogaster, Phenotype, 030104 developmental biology, Speech delay, Transfer RNA, Female, medicine.symptom, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9]
Abstract

We describe six persons from three families with three homozygous protein truncating variants in PUS7: c.89_90del (p.Thr30Lysfs(∗)20), c.1348C>T (p.Arg450(∗)), and a deletion of the penultimate exon 15. All these individuals have intellectual disability with speech delay, short stature, microcephaly, and aggressive behavior. PUS7 encodes the RNA-independent pseudouridylate synthase 7. Pseudouridylation is the most abundant post-transcriptional modification in RNA, which is primarily thought to stabilize secondary structures of RNA. We show that the disease-related variants lead to abolishment of PUS7 activity on both tRNA and mRNA substrates. Moreover, pus7 knockout in Drosophila melanogaster results in a number of behavioral defects, including increased activity, disorientation, and aggressiveness supporting that neurological defects are caused by PUS7 variants. Our findings demonstrate that RNA pseudouridylation by PUS7 is essential for proper neuronal development and function.

Published
2018
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28. Genetics of autosomal recessive intellectual disability

Author

Rami Abou Jamra

Subjects
Exome sequencing, 0301 basic medicine, Pleiotropie, Population, Biology, Konsanguin, Low functional autism, 03 medical and health sciences, Pleiotropy, Consanguineous, Intellectual disability, Genetics, medicine, Heterogeneous, education, Low-Functioning Autismus, Genetics (clinical), Entwicklungsverzögerung, education.field_of_study, Heterozygot, Neurodevelopmental disorders, Schwerpunktthema: Intelligenzminderung, medicine.disease, Arid, Human genetics, 030104 developmental biology, Exom-Sequenzierung
Abstract

In the last few years, next-generation sequencing has led to enormous progress in deciphering monogenic forms of intellectual disability. Autosomal dominant intellectual disability (ADID) and X chromosomal intellectual disability (XLID) have been the focus of research. Apart from metabolic disorders, autosomal recessive intellectual disability (ARID) is still behind, probably because it is more heterogeneous and less prevalent in industrial populations. The prevalence of ARID in a cohort of affected children of an outbred population is estimated to be about 10%, with an upward tendency in still unclarified cases. The risk for ARID in children of first cousins or closer is a magnitude higher than for children of unrelated parents. Taken together, it seems that children of related parents are at a 2 to 3 times higher risk for ID. There are no prevalent ARID genes, pathways, or protein complexes and the functions of the affected proteins are very diverse and limited not only to neurological aspects. Thus, in a regular case, there is no reasoning for picking a few genes for a first diagnostic step, and a genetic diagnosis of ID in general, and ARID specifically, is better made using large panels or exome sequencing. In addition, in the last few months, evidence has been growing that many ARID genes are pleiotropic and that the resulting phenotypes may have a broad spectrum. For an exhaustive deciphering of the genetics of ARID, we suggest research at the level of single genes rather than large meta-analyses.„Next generation sequencing“ (NGS) führte in den letzten Jahren zu enormen Fortschritten bei der Entschlüsselung monogener Formen der geistigen Behinderung. Bisher standen die autosomal-dominante geistige Behinderung (ADID) und die X‑chromosomale geistige Behinderung (XLID) im Mittelpunkt der Forschung. Bis auf die Stoffwechseldefekte ist die autosomal-rezessive geistige Behinderung (ARID) weniger erforscht, wahrscheinlich weil sie heterogener ist und in den Industriebevölkerungen eine geringere Prävalenz aufweist. Die Prävalenz von ARID in einer Kohorte betroffener Kinder einer Outbred-Population wird auf etwa 10 % geschätzt, wobei eine Tendenz nach oben in noch ungeklärten Fällen zu erwarten ist. Das Risiko für ARID bei Kindern von Cousins und Cousinen ersten Grades oder näher verwandt scheint um ungefähr den Faktor 10 höher zu sein als bei Kindern von nichtverwandten Eltern. Nach Berücksichtigung anderer Ätiologien ist das Gesamtrisiko für ID bei Kindern verwandter Eltern etwa 2- bis 3-fach höher. Es gibt keine Gene, Signalwege oder Proteinkomplexe, welche auffällig häufig bei ARID betroffen sind. Die Funktionen der betroffenen Proteine sind sehr vielfältig und nicht nur auf neurologische Aspekte beschränkt. Daher ist in der Regel die Auswahl einiger Gene für einen ersten diagnostischen Schritt nicht gerechtfertigt. Eine genetische Diagnose eines Falles mit ID im Generellen und von ARID im Besonderen ist durch große Panels oder Exom-Sequenzierung zu stellen. In den letzten Monaten hat sich zudem gezeigt, dass viele ARID-Gene pleiotrop sind und die resultierenden Phänotypen ein breites Spektrum aufweisen können. Für eine vollständige Entschlüsselung der Genetik von ARID sind Untersuchungen an einzelnen Genen und weniger die großen Meta-Analysen erforderlich.

Published
2018
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29. Haploinsufficiency of CUX1 Causes Nonsyndromic Global Developmental Delay With Possible Catch-up Development

Author

Soo-Mi Park, Carlo Marcelis, Katrin Oberndorff, Benjamin Cogné, Diana Mitter, Constance T. R. M. Stumpel, Rami Abou Jamra, Konrad Platzer, Alexander P.A. Stegmann, Ingrid Simonic, Marie Vincent, Johannes R. Lemke, Jennifer Hague, Jasper J. van der Smagt, Hans Kristian Ploos van Amstel, and Servi J. C. Stevens

Subjects
0301 basic medicine, Genetics, medicine.medical_specialty, Neurology, Copy number analysis, Biology, medicine.disease, Phenotype, 03 medical and health sciences, 030104 developmental biology, Intellectual disability, medicine, Etiology, Neurology (clinical), Global developmental delay, Haploinsufficiency, Exome sequencing
Abstract

Objective Developmental delay (DD) with favorable intellectual outcome and mild intellectual disability (ID) are mostly considered to be of complex genetic and environmental origin, but, in fact, often remain unclear. We aimed at proving our assumption that also mild cases of DD and ID may be of monogenic etiology. Methods We clinically evaluated 8 individuals and performed exome sequencing or array copy number analysis and identified variants in CUX1 as the likely cause. In addition, we included a case from the public database, DECIPHER. Results All 9 individuals harbored heterozygous null-allele variants in CUX1, encoding the Cut-homeobox 1 transcription factor that is involved in regulation of dendritogenesis and cortical synapse formation in layer II to IV cortical neurons. Six variants arose de novo, while in one family the variant segregated with ID. Of the 9 included individuals, 2 were diagnosed with moderate ID, 3 with mild ID, and 3 showed a normal age-related intelligence at ages 4, 6, and 8 years after a previous history of significant DD. Interpretation Our results suggest that null-allele variants, and thus haploinsufficiency of CUX1, cause an isolated phenotype of DD or ID with possible catch-up development. This illustrates that such a developmental course is not necessarily genetic complex, but may also be attributed to a monogenic cause. Ann Neurol 2018;84:200-207.

Published
2018
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30. Clinical relevance of systematic phenotyping and exome sequencing in patients with short stature

Author

Cornelia Kraus, Christiane Zweier, Rami Abou Jamra, Patricia Klinger, Sarah Schuhmann, Nadine N. Hauer, Steffen Uebe, Heinrich Sticht, Christian Thiel, Christian Büttner, Helmuth-Günther Dörr, Arif B. Ekici, Karen E. Heath, Fulvia Ferrazzi, Bernt Popp, Antje Wiesener, Alfonso Hisado-Oliva, Erdmute Kunstmann, Anita Rauch, Martin Zenker, Eva Schoeller, Dagmar Wieczorek, André Reis, and Udo Trautmann

Subjects
0301 basic medicine, Male, Heterozygote, Genetic counseling, Medizin, 030209 endocrinology & metabolism, Bioinformatics, medicine.disease_cause, Short stature, growth, phenotypic spectrum, Whole Exome Sequencing, 03 medical and health sciences, 0302 clinical medicine, Exome Sequencing, medicine, Humans, Clinical significance, Original Research Article, whole-exome sequencing, Genetic Testing, Allele, Genetics (clinical), Exome sequencing, Genetic testing, Mutation, medicine.diagnostic_test, business.industry, High-Throughput Nucleotide Sequencing, Sequence Analysis, DNA, medicine.disease, Body Height, Pedigree, 030104 developmental biology, Phenotype, short stature, skeletal dysplasia, Dysplasia, Female, medicine.symptom, business
Abstract

Purpose Short stature is a common condition of great concern to patients and their families. Mostly genetic in origin, the underlying cause often remains elusive due to clinical and genetic heterogeneity. Methods We systematically phenotyped 565 patients where common nongenetic causes of short stature were excluded, selected 200 representative patients for whole-exome sequencing, and analyzed the identified variants for pathogenicity and the affected genes regarding their functional relevance for growth. Results By standard targeted diagnostic and phenotype assessment, we identified a known disease cause in only 13.6% of the 565 patients. Whole-exome sequencing in 200 patients identified additional mutations in known short-stature genes in 16.5% of these patients who manifested only part of the symptomatology. In 15.5% of the 200 patients our findings were of significant clinical relevance. Heterozygous carriers of recessive skeletal dysplasia alleles represented 3.5% of the cases. Conclusion A combined approach of systematic phenotyping, targeted genetic testing, and whole-exome sequencing allows the identification of the underlying cause of short stature in at least 33% of cases, enabling physicians to improve diagnosis, treatment, and genetic counseling. Exome sequencing significantly increases the diagnostic yield and consequently care in patients with short stature.

Published
2017

31. GRIN2Bencephalopathy: novel findings on phenotype, variant clustering, functional consequences and treatment aspects

Author

Arndt Rolfs, Douglas R. Smith, Hongjie Yuan, Markus Wolff, Eirik Frengen, Sarah E Parisotto, Mark A. Tarnopolsky, John Millichap, Katherine L. Helbig, Christian Korff, Lutz Dondit, Anna-Elina Lehesjoki, Alison M. Muir, Brad T. Tinkle, Heather C Mefford, Bodo Laube, Anne T. Berg, Wen-Hann Tan, Kelly L. Jones, Floor E. Jansen, Christine M. Stanley, Candace T. Myers, Isabelle De Bie, John A. Lawson, Henrike O. Heyne, Wenjuan Chen, David Neal Franz, Julie R. Jones, Elysa J. Marco, Nataliya Di Donato, Cyril Mignot, Jasper J. van der Smagt, Stephen F. Traynelis, Tarja Linnankivi, Tim M. Strom, Hirofumi Kusumoto, Rena Vanzo, Petter Strømme, Uffe Birk Jensen, Amy Lacroix, Darius J Adams, Chun Hu, Boris Keren, Sha Tang, Richard J. Leventer, Johannes R. Lemke, Levinus A. Bok, Helio Pedro, Rami Abou Jamra, Dianalee McKnight, Ethan M. Goldberg, Tony Roscioli, Lauren Brady, Konrad Platzer, Philippe Major, Amy Decker, Anup D. Patel, Marcia C. Willing, Ingrid E. Scheffer, Mark Mintz, Eva H. Brilstra, Carolina Courage, Lynette G. Sadleir, Alexander Winschel, William B. Dobyns, Stephanie Fox, Emmanuelle Ranza, Saskia Biskup, Dennis Döcker, Judith D. Ranells, Rikke S. Møller, Elaine H. Zackai, Hannah Schütz, Mieke M. van Haelst, Christel Depienne, Medicum, Research Programme for Molecular Neurology, Department of Medical and Clinical Genetics, Research Programs Unit, Neuroscience Center, Anna-Elina Lehesjoki / Principal Investigator, University of Helsinki, Children's Hospital, Clinicum, Lastenneurologian yksikkö, HUS Children and Adolescents, Amsterdam Reproduction & Development (AR&D), Human genetics, and Amsterdam Neuroscience - Complex Trait Genetics

Subjects
0301 basic medicine, INTELLECTUAL DISABILITY, Brain Diseases/drug therapy/genetics, Pathogenic GRIN2B mutations, AUTISM SPECTRUM DISORDERS, Cortical visual impairment, Bioinformatics, Clustering of missense variants, 3124 Neurology and psychiatry, Epilepsy, 0302 clinical medicine, Channelopathy, NMDA RECEPTORS, Receptors, Intellectual disability, Polymicrogyria, Genetics(clinical), Molecular Targeted Therapy, Genetics (clinical), ddc:618, biology, Epileptic encephalopathy, Precision medicine, 1184 Genetics, developmental biology, physiology, Magnetic Resonance Imaging, Memantine/therapeutic use, Hypotonia, 3. Good health, N-Methyl-D-Aspartate/antagonists & inhibitors/genetics/metabolism, Phenotype, medicine.symptom, Heterozygote, GENES, Mutation/genetics, MIGRATION, Clustering Of Missense Variants, Epileptic Encephalopathy, Pathogenic Grin2b Mutations, Precision Medicine, Encephalopathy, Neuroimaging, Article, 03 medical and health sciences, Journal Article, Genetics, medicine, Humans, NEURODEVELOPMENTAL DISORDERS, business.industry, 3112 Neurosciences, medicine.disease, INDIVIDUALS, 030104 developmental biology, DE-NOVO MUTATIONS, FOCAL EPILEPSY, SUBUNIT, biology.protein, Autism, GRIN2B, 3111 Biomedicine, business, 030217 neurology & neurosurgery
Abstract

BACKGROUND: We aimed for a comprehensive delineation of genetic, functional and phenotypic aspects of GRIN2B encephalopathy and explored potential prospects of personalised medicine.METHODS: Data of 48 individuals with de novo GRIN2B variants were collected from several diagnostic and research cohorts, as well as from 43 patients from the literature. Functional consequences and response to memantine treatment were investigated in vitro and eventually translated into patient care.RESULTS: Overall, de novo variants in 86 patients were classified as pathogenic/likely pathogenic. Patients presented with neurodevelopmental disorders and a spectrum of hypotonia, movement disorder, cortical visual impairment, cerebral volume loss and epilepsy. Six patients presented with a consistent malformation of cortical development (MCD) intermediate between tubulinopathies and polymicrogyria. Missense variants cluster in transmembrane segments and ligand-binding sites. Functional consequences of variants were diverse, revealing various potential gain-of-function and loss-of-function mechanisms and a retained sensitivity to the use-dependent blocker memantine. However, an objectifiable beneficial treatment response in the respective patients still remains to be demonstrated.CONCLUSIONS: In addition to previously known features of intellectual disability, epilepsy and autism, we found evidence that GRIN2B encephalopathy is also frequently associated with movement disorder, cortical visual impairment and MCD revealing novel phenotypic consequences of channelopathies.

Published
2017
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32. Hypomorphic Pathogenic Variants in TAF13 Are Associated with Autosomal-Recessive Intellectual Disability and Microcephaly

Author

Roberto Colombo, Franz Wolfgang Hirsch, Natalie Wohlfahrt, Irwin Davidson, André Reis, Rami Abou Jamra, Johannes Schumacher, Rebecca Buchert, Igor Martianov, Hasan Tawamie, Luigi Janiri, Steffen Uebe, Heinrich Sticht, Gabrielle Mengus, Fulvia Ferrazzi, MENGUS, Gabrielle, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Institut de Génétique et de Biologie Moléculaire et Cellulaire (IGBMC), Université de Strasbourg (UNISTRA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), University of Tübingen, Università cattolica del Sacro Cuore = Catholic University of the Sacred Heart [Roma] (Unicatt), University Hospital Leipzig, and University of Bonn

Subjects
Male, 0301 basic medicine, Microcephaly, Transcription, Genetic, Protein Conformation, [SDV]Life Sciences [q-bio], RNA polymerase II, Biology, 03 medical and health sciences, pathogenic variant, 0302 clinical medicine, Report, Gene expression, Genetics, medicine, Humans, Immunoprecipitation, Promoter Regions, Genetic, transcription factor IID, Gene, Alleles, TAF13, Genetics (clinical), Exome sequencing, TATA-Binding Protein Associated Factors, Gene knockdown, Genetic Variation, Infant, Promoter, medicine.disease, Pedigree, [SDV] Life Sciences [q-bio], 030104 developmental biology, intellectual disability, biology.protein, Female, Transcription Factor TFIID, RNA-seq, Transcription factor II D, exome sequencing, 030217 neurology & neurosurgery
Abstract

International audience; In two independent consanguineous families each with two children affected by mild intellectual disability and microcephaly, we identified two homozygous missense variants (c.119T>A [p.Met40Lys] and c.92T>A [p.Leu31His]) in TATA-box-binding-protein-associated factor 13 (TAF13). Molecular modeling suggested a pathogenic effect of both variants through disruption of the interaction between TAF13 and TAF11. These two proteins form a histone-like heterodimer that is essential for their recruitment into the general RNA polymerase II transcription factor IID (TFIID) complex. Co-immunoprecipitation in HeLa cells transfected with plasmids encoding TAF11 and TAF13 revealed that both variants indeed impaired formation of the TAF13-TAF11 heterodimer, thus confirming the protein modeling analysis. To further understand the functional role of TAF13, we performed RNA sequencing of neuroblastoma cell lines upon TAF13 knockdown. The transcriptional profile showed significant deregulation of gene expression patterns with an emphasis on genes related to neuronal and skeletal functions and those containing E-box motives in their promoters. Here, we expand the spectrum of TAF-associated phenotypes and highlight the importance of TAF13 in neuronal functions.

Published
2017
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33. Mutations of familial Mediterranean fever in Syrian patients and controls: Evidence for high carrier rate

Author

Rami A. Jarjour and Rami Abou Jamra

Subjects
0301 basic medicine, medicine.medical_specialty, Abdominal pain, Population, Familial Mediterranean fever, Single-nucleotide polymorphism, medicine.disease_cause, Gastroenterology, 03 medical and health sciences, 0302 clinical medicine, Synovitis, Internal medicine, Genetics, medicine, education, 030203 arthritis & rheumatology, education.field_of_study, Mutation, business.industry, medicine.disease, MEFV, Penetrance, 030104 developmental biology, medicine.symptom, business
Abstract

Background Familial Mediterranean fever (FMF) is an autosomal recessive disorder caused by mutations in Mediterranean FeVer ( MEFV ) gene and is characterized by recurrent attacks of abdominal pain, synovitis and pleuritis. Methods and results To determine the impact of mutations in MEFV on the Syrian population, we ascertained the distribution of MEFV mutations in 358 healthy controls and 302 FMF patients from Syria. Mutation detection allowed the identification of 14 different MEFV mutations in the healthy controls. The most dominant mutations detected were E148Q (7.68%), V726A (2.5%), M694I (1.68%), R408Q (1.54%), P369S (1.54%), and M694V (1.12%). In patients, M694V is the most common mutation identified in the Syrian FMF patients (24.1%), followed by E148Q (13.5%), V726A (11.4%), M680I(G/C) (10.3%), and M694I (8.2%). Conclusions our data show that the carrier rate in healthy Syrian individuals is at least 1:3.3 (30.2%) and thus one of the highest and we confirm that some of the mentioned mutations and probably further genetic variants have variable penetrance or that FMF is underdiagnosed in the Syrian population.

Published
2017
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34. Genetic basis of neurodevelopmental disorders in 103 Jordanian families

Author

Olaf Riess, Peter Bauer, Rebecca Buchert, Sana' A. S. Al Hait, Wael Al‐Ameri, Moath Hamadallah, Marc Sturm, Anis Al‐Nazer, Omar Nafie, Rami Abou Jamra, Beate Kootz, Lucia Laugwitz, Linda Sofan, Philipp A. Koch, Johannes Hanselmann, Tala Issa, Tobias B. Haack, Aya Baraghiti, Julia Sommerfeld, Angelika Riess, Ayman J. Alfrook, and Tawfiq Froukh

Subjects
0301 basic medicine, Male, DNA Copy Number Variations, 030105 genetics & heredity, Biology, Frameshift mutation, 03 medical and health sciences, Neurodevelopmental disorder, Intellectual Disability, Intellectual disability, Exome Sequencing, Genetics, medicine, Missense mutation, Humans, Exome, Copy-number variation, Frameshift Mutation, Genetics (clinical), Exome sequencing, Jordan, Siblings, Homozygote, medicine.disease, Pedigree, 030104 developmental biology, Neurodevelopmental Disorders, Female, Trinucleotide repeat expansion, Candidate Disease Gene
Abstract

We recruited 103 families from Jordan with neurodevelopmental disorders (NDD) and patterns of inheritance mostly suggestive of autosomal recessive inheritance. In each family, we investigated at least one affected individual using exome sequencing and an in-house diagnostic variant interpretation pipeline including a search for copy number variation. This approach led us to identify the likely molecular defect in established disease genes in 37 families. We could identify 25 pathogenic nonsense and 11 missense variants as well as 3 pathogenic copy number variants and 1 repeat expansion. Notably, 11 of the disease-causal variants occurred de novo. In addition, we prioritized a homozygous frameshift variant in PUS3 in two sisters with intellectual disability. To our knowledge, PUS3 has been postulated only recently as a candidate disease gene for intellectual disability in a single family with three affected siblings. Our findings provide additional evidence to establish loss of PUS3 function as a cause of intellectual disability.

Published
2019

35. CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum

Author

Enrico D.H. Konrad, Niels Nardini, Almuth Caliebe, Inga Nagel, Dana Young, Gabriella Horvath, Stephanie L. Santoro, Christine Shuss, Alban Ziegler, Dominique Bonneau, Marlies Kempers, Rolph Pfundt, Eric Legius, Arjan Bouman, Kyra E. Stuurman, Katrin Õunap, Sander Pajusalu, Monica H. Wojcik, Georgia Vasileiou, Gwenaël Le Guyader, Hege M. Schnelle, Siren Berland, Evelien Zonneveld-Huijssoon, Simone Kersten, Aditi Gupta, Patrick R. Blackburn, Marissa S. Ellingson, Matthew J. Ferber, Radhika Dhamija, Eric W. Klee, Meriel McEntagart, Klaske D. Lichtenbelt, Amy Kenney, Samantha A. Vergano, Rami Abou Jamra, Konrad Platzer, Mary Ella Pierpont, Divya Khattar, Robert J. Hopkin, Richard J. Martin, Marjolijn C.J. Jongmans, Vivian Y. Chang, Julian A. Martinez-Agosto, Outi Kuismin, Mitja I. Kurki, Olli Pietiläinen, Aarno Palotie, Timothy J. Maarup, Diana S. Johnson, Katja Venborg Pedersen, Lone W. Laulund, Sally A. Lynch, Moira Blyth, Katrina Prescott, Natalie Canham, Rita Ibitoye, Eva H. Brilstra, Marwan Shinawi, Emily Fassi, Heinrich Sticht, Anne Gregor, Hilde Van Esch, Christiane Zweier, Graduate School, Clinical Genetics, Institute for Molecular Medicine Finland, Genomics of Neurological and Neuropsychiatric Disorders, University of Helsinki, Center for Population, Health and Society, Centre of Excellence in Complex Disease Genetics, and Aarno Palotie / Principal Investigator

Subjects
Male, CCCTC-Binding Factor, Developmental Disabilities, lnfectious Diseases and Global Health Radboud Institute for Molecular Life Sciences [Radboudumc 4], Transcriptome, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual disability, Drosophila Proteins, Missense mutation, TOOL, Genetics(clinical), Child, Genetics (clinical), Genetics & Heredity, Genetics, 0303 health sciences, biology, GENE ONTOLOGY, neurodevelopmental disorders, 1184 Genetics, developmental biology, physiology, HUMANS, Chromatin, 3. Good health, DROSOPHILA, Drosophila melanogaster, intellectual disability, LIBRARY, Female, INACTIVATION, Life Sciences & Biomedicine, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], EXPRESSION, DATABASE, Mutation, Missense, Article, Young Adult, 03 medical and health sciences, Exome Sequencing, medicine, Animals, Gene, 030304 developmental biology, Science & Technology, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Gene Expression Profiling, biology.organism_classification, medicine.disease, CTCF, Gene Expression Regulation, DE-NOVO MUTATIONS, Mutation, 030217 neurology & neurosurgery, Transcription Factors, chromatin organization
Abstract

PURPOSE: Pathogenic variants in the chromatin organizer CTCF were previously reported in seven individuals with a neurodevelopmental disorder (NDD). METHODS: Through international collaboration we collected data from 39 subjects with variants in CTCF. We performed transcriptome analysis on RNA from blood samples and utilized Drosophila melanogaster to investigate the impact of Ctcf dosage alteration on nervous system development and function. RESULTS: The individuals in our cohort carried 2 deletions, 8 likely gene-disruptive, 2 splice-site, and 20 different missense variants, most of them de novo. Two cases were familial. The associated phenotype was of variable severity extending from mild developmental delay or normal IQ to severe intellectual disability. Feeding difficulties and behavioral abnormalities were common, and variable other findings including growth restriction and cardiac defects were observed. RNA-sequencing in five individuals identified 3828 deregulated genes enriched for known NDD genes and biological processes such as transcriptional regulation. Ctcf dosage alteration in Drosophila resulted in impaired gross neurological functioning and learning and memory deficits. CONCLUSION: We significantly broaden the mutational and clinical spectrum ofCTCF-associated NDDs. Our data shed light onto the functional role of CTCF by identifying deregulated genes and show that Ctcf alterations result in nervous system defects in Drosophila. ispartof: GENETICS IN MEDICINE vol:21 issue:12 pages:2723-2733 ispartof: location:United States status: published

Published
2019
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36. Disruptive mutations in TANC2 define a neurodevelopmental syndrome associated with psychiatric disorders

Author

Charles E. Schwartz, Marjolein H. Willemsen, Saadet Mercimek-Andrews, Amy B. Wilfert, Hugo J. Bellen, Alexander P.A. Stegmann, Tjitske Kleefstra, Pawel Stankiewicz, Benjamin Büttner, Hailun Ni, Rongjuan Zhao, Rami Abou Jamra, Mariëtte J.V. Hoffer, Kristin Herman, Marjan M. Weiss, Heather C Mefford, Huidan Wu, Deanna J. Erwin, Zhengmao Hu, Claudia A. L. Ruivenkamp, Helger G. Yntema, Cindy Colson, Alessandra Murgia, Maria Bottitta, Jane Juusola, Tianyun Wang, Stephen M. Malone, Kun Xia, Baosheng Zhu, Nicolas Richard, Jozef Gecz, Elisa Bettella, Tuula Rinne, Raphael Bernier, Emilia K. Bijlsma, Michael F. Wangler, Shinya Yamamoto, Brigid M. Regan, Sharayu Jangam, Bregje W.M. van Bon, Jill A. Rosenfeld, Kendra Hoekzema, Cenying Liu, Shweta U. Dhar, Stefano Sartori, Boris Keren, Hui Guo, Lucia Castiglia, Servi J. C. Stevens, Corrado Romano, Min Long, Tomasz J. Nowakowski, Evan E. Eichler, Jan Maarten Cobben, Alison M. Muir, Lisa Emrick, Quinten Waisfisz, Wenjing Zhao, Jonathan C. Andrews, Ingrid E. Scheffer, Bing Bai, Madelyn A. Gillentine, Paul C. Marcogliese, Fan Xia, Han G. Brunner, Alexandra Afenjar, Academic Medical Center, MUMC+: DA KG Polikliniek (9), MUMC+: DA KG Lab Centraal Lab (9), RS: GROW - R4 - Reproductive and Perinatal Medicine, MUMC+: DA Klinische Genetica (5), Klinische Genetica, Chinese Academy of Forestry, University Hospital of Padua, Baylor College of Medicine (BCM), Baylor University, Texas Children's Hospital [Houston, USA], Central South University [Changsha], University of California, Washington University School of Medicine in St. Louis, Washington University in Saint Louis (WUSTL), Department of Genome Sciences [Seattle] (GS), University of Washington [Seattle], Radboud University Medical Center [Nijmegen], Maastricht University Medical Centre (MUMC), Maastricht University [Maastricht], Ecosystèmes méditerranéens et risques (UR EMAX), Centre national du machinisme agricole, du génie rural, des eaux et forêts (CEMAGREF), Service de Génétique [CHU Caen], Université de Caen Normandie (UNICAEN), Normandie Université (NU)-Normandie Université (NU)-CHU Caen, Normandie Université (NU)-Tumorothèque de Caen Basse-Normandie (TCBN)-Tumorothèque de Caen Basse-Normandie (TCBN), Biologie, génétique et thérapies ostéoarticulaires et respiratoires (BIOTARGEN), Normandie Université (NU)-Normandie Université (NU), The Greenwood Genetic Center, Istituto di Ricovero e Cura a Carattere Scientifico (IRCCS), Fondazione 'Istituto Neurologico Nazionale C. Mondino', Centre de Recherche de l'Institut du Cerveau et de la Moelle épinière (CRICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), CHU Trousseau [APHP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Kunming University of Science and Technology (KMUST), The Hospital for sick children [Toronto] (SickKids), University of Toronto, GeneDx [Gaithersburg, MD, USA], Universität Leipzig [Leipzig], University of Melbourne, Queensland Institute of Medical Research, University of Adelaide, Emma Children’s Hospital, Vrije Universiteit Amsterdam [Amsterdam] (VU), Leiden University Medical Center (LUMC), The Chinese University of Hong Kong [Hong Kong], and Human genetics

Subjects
0301 basic medicine, Proband, Male, Genetics of the nervous system, Developmental Disabilities, General Physics and Astronomy, Muscle Proteins, medicine.disease_cause, ANNOTATION, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Whole Exome Sequencing, Craniofacial Abnormalities, Epilepsy, 0302 clinical medicine, Postsynaptic potential, Intellectual disability, Drosophila Proteins, lcsh:Science, Child, SYNAPTIC DEVELOPMENT, Neurons, Mutation, Multidisciplinary, Behavior, Animal, Mental Disorders, Brain, Drosophila melanogaster, Child, Preschool, Behavioural genetics, Excitatory postsynaptic potential, Female, Neuroglia, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], Adult, medicine.medical_specialty, GENES, Adolescent, Science, Nerve Tissue Proteins, Article, General Biochemistry, Genetics and Molecular Biology, 03 medical and health sciences, Young Adult, All institutes and research themes of the Radboud University Medical Center, RESOURCE, Intellectual Disability, Exome Sequencing, medicine, Animals, Humans, Language Development Disorders, Autistic Disorder, Psychiatry, Preschool, [SDV.GEN]Life Sciences [q-bio]/Genetics, Behavior, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], business.industry, Animal, MEMORY, Membrane Proteins, Proteins, General Chemistry, medicine.disease, FRAMEWORK, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, DE-NOVO MUTATIONS, Neurodevelopmental Disorders, Neuronal development, Autism, lcsh:Q, business, Postsynaptic density, 030217 neurology & neurosurgery
Abstract

Postsynaptic density (PSD) proteins have been implicated in the pathophysiology of neurodevelopmental and psychiatric disorders. Here, we present detailed clinical and genetic data for 20 patients with likely gene-disrupting mutations in TANC2—whose protein product interacts with multiple PSD proteins. Pediatric patients with disruptive mutations present with autism, intellectual disability, and delayed language and motor development. In addition to a variable degree of epilepsy and facial dysmorphism, we observe a pattern of more complex psychiatric dysfunction or behavioral problems in adult probands or carrier parents. Although this observation requires replication to establish statistical significance, it also suggests that mutations in this gene are associated with a variety of neuropsychiatric disorders consistent with its postsynaptic function. We find that TANC2 is expressed broadly in the human developing brain, especially in excitatory neurons and glial cells, but shows a more restricted pattern in Drosophila glial cells where its disruption affects behavioral outcomes., Neurodevelopmental disorders (NDDs) are a heterogeneous group of diseases for which the genetic basis is still unknown in more than half of the cases. Here, the authors report a NDD associated with disruptive variants in the TANC2 gene and show that rols, the TANC2 homolog in flies, is required for synapse growth and function.

Published
2019
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37. Pathogenic WDFY3 variants cause neurodevelopmental disorders and opposing effects on brain size

Author

Meron Azage, David B. Everman, Brooke T. Smith, Steffen Syrbe, Stephen W. Scherer, Jennifer Keller-Ramey, Gregory M. Cooper, Verónica Martínez-Cerdeño, Susan M. Hiatt, Mathew J Wallis, Dmitriy Niyazov, Benjamin Büttner, Rami Abou Jamra, Ryan K. C. Yuen, Johannes R. Lemke, Natasha J Brown, Amber Begtrup, Richard E. Person, Barbara Kellam, Chloé Quélin, Heinrich Sticht, Laurence J. Walsh, Angelo Harlan De Crescenzo, Konstantinos Zarbalis, Jonathan B. Strober, Susan Walker, Alexios A Panoutsopoulos, Shuxi Liu, Diana Le Duc, Urania Kotzaeridou, Michael S. Hildebrand, Michael C. Pride, Eleonora Napoli, Jacqueline N. Crawley, Francis Jeshira Reynoso Santos, Katelyn Payne, Renee Bend, Sandra Yang, Megan T. Cho, Evdokia Anagnostou, Cecilia R Giulivi, Rhonda E. Schnur, Lori Orosco, Andreas Ziegler, Jan H Doering, Christèle Dubourg, Jill L. Silverman, Universität Leipzig [Leipzig], University of California [Davis] (UC Davis), University of California, GeneDx [Gaithersburg, MD, USA], Institut de Génétique et Développement de Rennes (IGDR), 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), Service de génétique clinique [Rennes], Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-CHU Pontchaillou [Rennes]-hôpital Sud, Shriners Hospitals for Children, U54 HD079125, National Institute of Child Health and Human Development, R21MH115347, National Institute of Mental Health, 286567, Simons Foundation, Nancy Lurie Marks Family Foundation, UM1HG007301, National Human Genome Research Institute, Clinician Scientist Programm, Medizinische Fakultät der Universität Leipzig, Shriners Hospitals for Children Postdoctoral Fellowship, The MIND Institute IDDRC, Universität Leipzig, University of California (UC), 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 ), and Université de Rennes (UR)-CHU Pontchaillou [Rennes]-hôpital Sud

Subjects
0301 basic medicine, Proband, Male, Microcephaly, Secondary, [SDV]Life Sciences [q-bio], Autophagy-Related Proteins, Medical and Health Sciences, Transgenic, Mice, 0302 clinical medicine, Intellectual disability, 2.1 Biological and endogenous factors, Aetiology, Child, Exome, ComputingMilieux_MISCELLANEOUS, Pediatric, Brain, Adaptor Proteins, Organ Size, Mental Health, WDFY3, Autism spectrum disorder, intellectual disability, brain size, Neurological, Female, medicine.symptom, Haploinsufficiency, Biotechnology, Protein Structure, Adolescent, Intellectual and Developmental Disabilities (IDD), Biology, neurodevelopmental delay, 03 medical and health sciences, Clinical Research, medicine, Genetics, Animals, Humans, Preschool, Neurology & Neurosurgery, Psychology and Cognitive Sciences, Macrocephaly, Signal Transducing, Neurosciences, Genetic Variation, medicine.disease, Stem Cell Research, Associative learning, Brain Disorders, 030104 developmental biology, Neurodevelopmental Disorders, Neurology (clinical), Neuroscience, 030217 neurology & neurosurgery
Abstract

The underpinnings of mild to moderate neurodevelopmental delay remain elusive, often leading to late diagnosis and interventions. Here, we present data on exome and genome sequencing as well as array analysis of 13 individuals that point to pathogenic, heterozygous, mostly de novo variants in WDFY3 (significant de novo enrichment P = 0.003) as a monogenic cause of mild and non-specific neurodevelopmental delay. Nine variants were protein-truncating and four missense. Overlapping symptoms included neurodevelopmental delay, intellectual disability, macrocephaly, and psychiatric disorders (autism spectrum disorders/attention deficit hyperactivity disorder). One proband presented with an opposing phenotype of microcephaly and the only missense-variant located in the PH-domain of WDFY3. Findings of this case are supported by previously published data, demonstrating that pathogenic PH-domain variants can lead to microcephaly via canonical Wnt-pathway upregulation. In a separate study, we reported that the autophagy scaffolding protein WDFY3 is required for cerebral cortical size regulation in mice, by controlling proper division of neural progenitors. Here, we show that proliferating cortical neural progenitors of human embryonic brains highly express WDFY3, further supporting a role for this molecule in the regulation of prenatal neurogenesis. We present data on Wnt-pathway dysregulation in Wdfy3-haploinsufficient mice, which display macrocephaly and deficits in motor coordination and associative learning, recapitulating the human phenotype. Consequently, we propose that in humans WDFY3 loss-of-function variants lead to macrocephaly via downregulation of the Wnt pathway. In summary, we present WDFY3 as a novel gene linked to mild to moderate neurodevelopmental delay and intellectual disability and conclude that variants putatively causing haploinsufficiency lead to macrocephaly, while an opposing pathomechanism due to variants in the PH-domain of WDFY3 leads to microcephaly.

Published
2019
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38. Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy

Author

Anne H. O’Donnell-Luria, Lynn S. Pais, Víctor Faundes, Jordan C. Wood, Abigail Sveden, Victor Luria, Rami Abou Jamra, Andrea Accogli, Kimberly Amburgey, Britt Marie Anderlid, Silvia Azzarello-Burri, Alice A. Basinger, Claudia Bianchini, Lynne M. Bird, Rebecca Buchert, Wilfrid Carre, Sophia Ceulemans, Perrine Charles, Helen Cox, Lisa Culliton, Aurora Currò, Florence Demurger, James J. Dowling, Benedicte Duban-Bedu, Christèle Dubourg, Saga Elise Eiset, Luis F. Escobar, Alessandra Ferrarini, Tobias B. Haack, Mona Hashim, Solveig Heide, Katherine L. Helbig, Ingo Helbig, Raul Heredia, Delphine Héron, Bertrand Isidor, Amy R. Jonasson, Pascal Joset, Boris Keren, Fernando Kok, Hester Y. Kroes, Alinoë Lavillaureix, Xin Lu, Saskia M. Maas, Gustavo H.B. Maegawa, Carlo L.M. Marcelis, Paul R. Mark, Marcelo R. Masruha, Heather M. McLaughlin, Kirsty McWalter, Esther U. Melchinger, Saadet Mercimek-Andrews, Caroline Nava, Manuela Pendziwiat, Richard Person, Gian Paolo Ramelli, Luiza L.P. Ramos, Anita Rauch, Caitlin Reavey, Alessandra Renieri, Angelika Rieß, Amarilis Sanchez-Valle, Shifteh Sattar, Carol Saunders, Niklas Schwarz, Thomas Smol, Myriam Srour, Katharina Steindl, Steffen Syrbe, Jenny C. Taylor, Aida Telegrafi, Isabelle Thiffault, Doris A. Trauner, Helio van der Linden, Silvana van Koningsbruggen, Laurent Villard, Ida Vogel, Julie Vogt, Yvonne G. Weber, Ingrid M. Wentzensen, Elysa Widjaja, Jaroslav Zak, Samantha Baxter, Siddharth Banka, Lance H. Rodan, Jeremy F. McRae, Stephen Clayton, Tomas W. Fitzgerald, Joanna Kaplanis, Elena Prigmore, Diana Rajan, Alejandro Sifrim, Stuart Aitken, Nadia Akawi, Mohsan Alvi, Kirsty Ambridge, Daniel M. Barrett, Tanya Bayzetinova, Philip Jones, Wendy D. Jones, Daniel King, Netravathi Krishnappa, Laura E. Mason, Tarjinder Singh, Adrian R. Tivey, Munaza Ahmed, Uruj Anjum, Hayley Archer, Ruth Armstrong, Jana Awada, Meena Balasubramanian, Diana Baralle, Angela Barnicoat, Paul Batstone, David Baty, Chris Bennett, Jonathan Berg, Birgitta Bernhard, A. Paul Bevan, Maria Bitner-Glindzicz, Edward Blair, Moira Blyth, David Bohanna, Louise Bourdon, David Bourn, Lisa Bradley, Angela Brady, Simon Brent, Carole Brewer, Kate Brunstrom, David J. Bunyan, John Burn, Natalie Canham, Bruce Castle, Kate Chandler, Elena Chatzimichali, Deirdre Cilliers, Angus Clarke, Susan Clasper, Jill Clayton-Smith, Virginia Clowes, Andrea Coates, Trevor Cole, Irina Colgiu, Amanda Collins, Morag N. Collinson, Fiona Connell, Nicola Cooper, Lara Cresswell, Gareth Cross, Yanick Crow, Mariella D’Alessandro, Tabib Dabir, Rosemarie Davidson, Sally Davies, Dylan de Vries, John Dean, Charu Deshpande, Gemma Devlin, Abhijit Dixit, Angus Dobbie, Alan Donaldson, Dian Donnai, Deirdre Donnelly, Carina Donnelly, Angela Douglas, Sofia Douzgou, Alexis Duncan, Jacqueline Eason, Sian Ellard, Ian Ellis, Frances Elmslie, Karenza Evans, Sarah Everest, Tina Fendick, Richard Fisher, Frances Flinter, Nicola Foulds, Andrew Fry, Alan Fryer, Carol Gardiner, Lorraine Gaunt, Neeti Ghali, Richard Gibbons, Harinder Gill, Judith Goodship, David Goudie, Emma Gray, Andrew Green, Philip Greene, Lynn Greenhalgh, Susan Gribble, Rachel Harrison, Lucy Harrison, Victoria Harrison, Rose Hawkins, Liu He, Stephen Hellens, Alex Henderson, Sarah Hewitt, Lucy Hildyard, Emma Hobson, Simon Holden, Muriel Holder, Susan Holder, Georgina Hollingsworth, Tessa Homfray, Mervyn Humphreys, Jane Hurst, Ben Hutton, Stuart Ingram, Melita Irving, Lily Islam, Andrew Jackson, Joanna Jarvis, Lucy Jenkins, Diana Johnson, Elizabeth Jones, Dragana Josifova, Shelagh Joss, Beckie Kaemba, Sandra Kazembe, Rosemary Kelsell, Bronwyn Kerr, Helen Kingston, Usha Kini, Esther Kinning, Gail Kirby, Claire Kirk, Emma Kivuva, Alison Kraus, Dhavendra Kumar, V. K. Ajith Kumar, Katherine Lachlan, Wayne Lam, Anne Lampe, Caroline Langman, Melissa Lees, Derek Lim, Cheryl Longman, Gordon Lowther, Sally A. Lynch, Alex Magee, Eddy Maher, Alison Male, Sahar Mansour, Karen Marks, Katherine Martin, Una Maye, Emma McCann, Vivienne McConnell, Meriel McEntagart, Ruth McGowan, Kirsten McKay, Shane McKee, Dominic J. McMullan, Susan McNerlan, Catherine McWilliam, Sarju Mehta, Kay Metcalfe, Anna Middleton, Zosia Miedzybrodzka, Emma Miles, Shehla Mohammed, Tara Montgomery, David Moore, Sian Morgan, Jenny Morton, Hood Mugalaasi, Victoria Murday, Helen Murphy, Swati Naik, Andrea Nemeth, Louise Nevitt, Ruth Newbury-Ecob, Andrew Norman, Rosie O’Shea, Caroline Ogilvie, Kai-Ren Ong, Soo-Mi Park, Michael J. Parker, Chirag Patel, Joan Paterson, Stewart Payne, Daniel Perrett, Julie Phipps, Daniela T. Pilz, Martin Pollard, Caroline Pottinger, Joanna Poulton, Norman Pratt, Katrina Prescott, Sue Price, Abigail Pridham, Annie Procter, Hellen Purnell, Oliver Quarrell, Nicola Ragge, Raheleh Rahbari, Josh Randall, Julia Rankin, Lucy Raymond, Debbie Rice, Leema Robert, Eileen Roberts, Jonathan Roberts, Paul Roberts, Gillian Roberts, Alison Ross, Elisabeth Rosser, Anand Saggar, Shalaka Samant, Julian Sampson, Richard Sandford, Ajoy Sarkar, Susann Schweiger, Richard Scott, Ingrid Scurr, Ann Selby, Anneke Seller, Cheryl Sequeira, Nora Shannon, Saba Sharif, Charles Shaw-Smith, Emma Shearing, Debbie Shears, Eamonn Sheridan, Ingrid Simonic, Roldan Singzon, Zara Skitt, Audrey Smith, Kath Smith, Sarah Smithson, Linda Sneddon, Miranda Splitt, Miranda Squires, Fiona Stewart, Helen Stewart, Volker Straub, Mohnish Suri, Vivienne Sutton, Ganesh Jawahar Swaminathan, Elizabeth Sweeney, Kate Tatton-Brown, Cat Taylor, Rohan Taylor, Mark Tein, I. Karen Temple, Jenny Thomson, Marc Tischkowitz, Susan Tomkins, Audrey Torokwa, Becky Treacy, Claire Turner, Peter Turnpenny, Carolyn Tysoe, Anthony Vandersteen, Vinod Varghese, Pradeep Vasudevan, Parthiban Vijayarangakannan, Emma Wakeling, Sarah Wallwark, Jonathon Waters, Astrid Weber, Diana Wellesley, Margo Whiteford, Sara Widaa, Sarah Wilcox, Emily Wilkinson, Denise Williams, Nicola Williams, Louise Wilson, Geoff Woods, Christopher Wragg, Michael Wright, Laura Yates, Michael Yau, Chris Nellåker, Michael Parker, Helen V. Firth, Caroline F. Wright, David R. FitzPatrick, Jeffrey C. Barrett, Matthew E. Hurles, Department of Medicine 1, Friedrich-Alexander Universität Erlangen-Nürnberg (FAU), Center for Medical Genetics, Istituto di Scienze e Tecnologie della Cognizione, Consiglio Nazionale delle Ricerche (ISTC, CNR), Istituto di Scienze e Tecnologie della Cognizione, Station biologique de Roscoff [Roscoff] (SBR), Université Pierre et Marie Curie - Paris 6 (UPMC)-Centre National de la Recherche Scientifique (CNRS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Génétique médicale [Centre Hospitalier de Vannes], Centre hospitalier Bretagne Atlantique (Morbihan) (CHBA), Department of Pediatrics, University of Michigan [Ann Arbor], University of Michigan System-University of Michigan System, Centre de Génétique Chromosomique [Hôpital Saint Vincent de Paul], Hôpital Saint Vincent de Paul-Groupement des Hôpitaux de l'Institut Catholique de Lille (GHICL), Université catholique de Lille (UCL)-Université catholique de Lille (UCL), 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 ), Service de génétique médicale, Centre Hospitalier Universitaire Vaudois [Lausanne] (CHUV), Institute of Human Genetics, Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz Zentrum München = German Research Center for Environmental Health, Groupe de Recherche Clinique : Déficience Intellectuelle et Autisme (GRC), Université Pierre et Marie Curie - Paris 6 (UPMC), Children’s Hospital of Philadelphia (CHOP ), Service de Génétique Médicale, Centre hospitalier universitaire de Nantes (CHU Nantes), Department of Public Health Sciences, Karolinska Institutet [Stockholm], Department of Molecular and Human Genetics, Baylor College of Medicine (BCM), Baylor University-Baylor University, Institute of Medical Genetics, Universität Zürich [Zürich] = University of Zurich (UZH), Università degli Studi di Camerino = University of Camerino (UNICAM), Centre Hospitalier Régional Universitaire [Lille] (CHRU Lille), University of Oxford, GeneDx [Gaithersburg, MD, USA], Department of Clinical Genetics (Academic Medical Center, University of Amsterdam), VU University Medical Center [Amsterdam], 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), Department of Clinical Genetics, Aarhus University Hospital, Boston Children's Hospital, Wellcome Trust Genome Campus, The Wellcome Trust Sanger Institute [Cambridge], Institute of Biomedical Engineering [Oxford] (IBME), Climatic Research Unit, University of East Anglia [Norwich] (UEA), Imperial College London, St Mary's Hospital, East Anglian Medical Genetics Service, Cytogenetics Laboratory, Addenbrooke's Hospital, Sheffield Children's NHS Foundation Trust, Regional Genetic Service, St Mary's Hospital, Manchester, Genetics, University of Southampton, Great Ormond Street Hospital for Children [London] (GOSH), Yorkshire Regional Clinical Genetics Service, Chapel Allerton Hospital, Molecular and Clinical Medicine [Dundee, UK] (School of Medicine), University of Dundee [UK]-Ninewells Hospital & Medical School [Dundee, UK], Department of Clinical Genetics, Oxford Regional Genetics Service, The Churchill hospital, North West Thames Regional Genetics, Northwick Park Hospital, Royal Devon & Exeter Hospital, Wessex Clinical Genetics Service, Wessex clinical genetics service, Manchester University NHS Foundation Trust (MFT), West Midlands Regional Genetics Service, Birmingham Women's and Children's NHS Foundation Trust, Our Lady's hospital for Sick Children, Our Lady's Hospital for Sick Children, Guy's Hospital [London], University Hospitals Leicester, University of Edinburgh, Belfast City Hospital, Ferguson-Smith Centre for Clinical Genetics, Yorkhill Hospitals, Institute of Medical Genetics, Heath Park, Cardiff, The London Clinic, Nottingham City Hospital, Clinical Genetics Department, St Michael's Hospital, Department of Genetic Medicine, Nottingham Clinical Genetics Service, Nottingham University Hospitals NHS Trust (NUH), Royal Devon and Exeter Foundation Trust, Histopathology, St. George's Hospital, Teesside Genetics Unit, James Cook University (JCU), Kansas State University, Liverpool Women's NHS Foundation Trust, Department of Medical Genetics, HMNC Brain Health, North West Thames Regional Genetics Service, Northwick Park Hospital, Harrow, Leicester Royal Infirmary, University Hospitals Leicester-University Hospitals Leicester, Ninewells Hospital and Medical School [Dundee], Academic Centre on Rare Diseases (ACoRD), University College Dublin [Dublin] (UCD), Oxford Brookes University, Institute of medicinal plant development, Chinese Academy of Medical Sciences, Newcastle Upon Tyne Hospitals NHS Trust, Service d'explorations fonctionnelles respiratoires [Lille], Department of Computer Science - Trinity College Dublin, University of Dublin, Department of Clinical Genetics (Sheffield Children’s NHS Foundation Trust), Division of Medical & Molecular Genetics, NHS Greater Glasgow & Clyde [Glasgow] (NHSGGC), Department of Clinical Genetics [Churchill Hospital], Churchill Hospital Oxford Centre for Haematology, Weizmann Institute of Science [Rehovot, Israël], Southampton General Hospital, Western General Hospital, Head of the Department of Medical Genetics, University of Birmingham [Birmingham], SW Thames Regional Genetics Service, St Georgeâ™s University of London, London, Institut Cochin (IC UM3 (UMR 8104 / U1016)), Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), All Wales Medical Genetics Services, Singleton Hospital, Central Manchester University Hospitals NHS Foundation Trust, University of North Texas (UNT), Clinical Genetics, Northern Genetics Service, Newcastle University [Newcastle], United Kingdom Met Office [Exeter], Institute of Medical Genetics (University Hospital of Wales), University Hospital of Wales (UHW), West Midlands Regional Genetics Laboratory and Clinical Genetics Unit, Birmingham Women's Hospital, Laboratory of Molecular Genetics, National Institute of Child Health and Human Development, National Institutes of Health, Department of Genetics, Cell- and Immunobiology, Semmelweis University, University Hospitals Bristol, Marketing (MKT), EESC-GEM Grenoble Ecole de Management, Addenbrookes Hospital, West of Scotland Genetics Service (Queen Elizabeth University Hospital), University Hospital Birmingham Queen Elizabeth, Department of Clnical Genetics, Chapel Allerton Hospital, Department of Clinical Genetics, Northampton General Hospital, Northampton, Royal Devon and Exeter Hospital [Exeter, UK] (RDEH), Guy's and St Thomas' Hospital [London], School of Computer Science, Bangor University, University Hospital Southampton, Clinical Genetics Unit, St Georges, University of London, Medical Genetics, Cardiff University, Research and Development, Futurelab, Nottingham Regional Genetics Service [Nottingham, UK], Nottingham University Hospitals NHS Trust (NUH)-City Hospital Campus [Nottingham, UK], University of St Andrews [Scotland], Clinical Genetics Service, Nottingham University Hospitals NHS Trust - City Hospital Campus, West Midlands Regional Genetics Unit, Department of Neurology, Johns Hopkins University (JHU), Oxford University Hospitals NHS Trust, St James's University Hospital, Leeds Teaching Hospitals NHS Trust, Addenbrooke's Hospital, Cambridge University NHS Trust, Institute of Human Genetics, Newcastle, Division of Biological Stress Response [Amsterdam, The Netherlands], The Netherlands Cancer Institute [Amsterdam, The Netherlands], Johns Hopkins Bloomberg School of Public Health [Baltimore], Birmingham Women’s Hospital, Department of Genetics, Portuguese Oncology Institute, Molecular Genetics, IWK Health Centre, IWK health centre, North West london hospitals NHS Trust, Department of Clinical Genetics (Queen Elizabeth University Hospital, Glasgow), Queen Elizabeth University Hospital (Glasgow), Birmingham women's hospital, Birmingham, Ethox Centre, Department of Public Health and Primary Health Care, University of Oxford, Badenoch Building, Old Road Campus, Headington, R01 HD091846, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Human Genome Research Institute, National Institutes of Health’s National Institute of Child Health and Human Development, Boston Children’s Hospital Faculty Development Fellowship, UM1HG008900, Broad Center for Mendelian Genomics, Chile’s National Commission for Scientific and Technological Research, DFG WE4896/3-1, German Research Society, WT 100127, Health Innovation Challenge Fund, Comprehensive Clinical Research Network, Skaggs-Oxford Scholarship, 10/H0305/83, Cambridge South REC, REC GEN/284/12, Republic of Ireland, WT098051, Wellcome Sanger Institute, 72160007, Comisión Nacional de Investigación Científica y Tecnológica, Children's Hospital of Philadelphia, Technische Universität Kaiserslautern, 1DH1813319, Dietmar Hopp Stiftung, National Institute for Health Research, Department of Health & Social Care, Service de neurologie 1 [CHU Pitié-Salpétrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Sorbonne Université (SU), Hôpital Saint Vincent de Paul-GHICL, Université de Rennes 1 (UR1), Université de Rennes (UNIV-RENNES)-Université de Rennes (UNIV-RENNES)-Centre National de la Recherche Scientifique (CNRS)-Structure Fédérative de Recherche en Biologie et Santé de Rennes ( Biosit : Biologie - Santé - Innovation Technologique ), Technische Universität Munchen - Université Technique de Munich [Munich, Allemagne] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), Università degli Studi di Camerino (UNICAM), University of Oxford [Oxford], Institut National de la Santé et de la Recherche Médicale (INSERM)-Aix Marseille Université (AMU), Nottingham University Hospitals NHS Trust, Nottingham University Hospitals, SW Thames Regional Genetics Service, St George’s University of London, London, University Hospital of Wales, Grenoble Ecole de Management, Royal Devon and Exeter Hospital, City Hospital Campus [Nottingham, UK]-Nottingham University Hospitals NHS Trust [UK], ANS - Complex Trait Genetics, Human Genetics, ARD - Amsterdam Reproduction and Development, ACS - Pulmonary hypertension & thrombosis, Service de Neurologie [CHU Pitié-Salpêtrière], IFR70-CHU Pitié-Salpêtrière [AP-HP], GHICL-Hôpital Saint Vincent de Paul, Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Friedrich-Alexander d'Erlangen-Nuremberg, Assistance publique - Hôpitaux de Paris (AP-HP) (APHP)-CHU Pitié-Salpêtrière [APHP], Centre Hospitalier Bretagne Atlantique [Vannes], Technische Universität München [München] (TUM)-Helmholtz-Zentrum München (HZM)-German Research Center for Environmental Health, Service de Génétique et Cytogénétique [CHU Pitié-Salpêtrière], University of Zürich [Zürich] (UZH), Università di Camerino (UNICAM), Birmingham Women's Hospital Healthcare NHS Trust, University Hospitals of Leicester, Sheffield Children’s Hospital, Weizmann Institute of Science, and Grenoble Ecole de Management (GEM)

Subjects
0301 basic medicine, Male, Microcephaly, [SDV]Life Sciences [q-bio], Haploinsufficiency, autism, epilepsy, epileptic encephalopathy, global developmental delay, H3K4 methylation, intellectual disability, KMT2E, neurodevelopmental disorder, Adolescent, Adult, Child, Child, Preschool, DNA-Binding Proteins, Epilepsy, Female, Humans, Infant, Neurodevelopmental Disorders, Pedigree, Phenotype, Young Adult, Genetic Variation, Heterozygote, 0302 clinical medicine, Neurodevelopmental disorder, Intellectual disability, Global developmental delay, Genetics (clinical), ComputingMilieux_MISCELLANEOUS, Genetics, 0303 health sciences, Hypotonia, 030220 oncology & carcinogenesis, medicine.symptom, Rare cancers Radboud Institute for Health Sciences [Radboudumc 9], 03 medical and health sciences, Report, medicine, Journal Article, Expressivity (genetics), Preschool, 030304 developmental biology, [SDV.GEN]Life Sciences [q-bio]/Genetics, business.industry, Macrocephaly, medicine.disease, 030104 developmental biology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Autism, business, 030217 neurology & neurosurgery
Abstract

Contains fulltext : 206572.pdf (Publisher’s version ) (Open Access) We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities.

Published
2019
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40. Novel EXOSC3 pathogenic variant results in a mild course of neurologic disease with cerebellum involvement

Author

Dagmar Wieczorek, Silke Redler, Rami Abou Jamra, Jörg Schaper, Diana Le Duc, and Susanne Horn

Subjects
Male, Cerebellum, Pathology, medicine.medical_specialty, Heterozygote, Degeneration (medical), Disease, Compound heterozygosity, Young Adult, Cerebellar Diseases, Genetics, medicine, Humans, Child, Genetics (clinical), Genetic Association Studies, Exosome Multienzyme Ribonuclease Complex, business.industry, Siblings, Homozygote, RNA-Binding Proteins, General Medicine, medicine.disease, Phenotype, Pons, Hypoplasia, medicine.anatomical_structure, Mutation, Female, business, Neurocognitive
Abstract

EXOSC3-related autosomal recessive neurodevelopmental disorders are rare entities with variable clinical course and prognosis. They are characterized by hypoplasia of cerebellar structures and pons, degeneration of the anterior horn cells and motor as well as neurocognitive impairment. Phenotypic expression is variable with an overall poor outcome. Current research suggests clear genotype-phenotype correlations among EXOSC3-pathogenic-variants carriers. Homozygosity for the EXOSC3 variant c.395A > C, p.(Asp132Ala) is proposed to lead to a rather mild phenotype compared to compound-heterozygous EXOSC3-pathogenic-variants carriers with lethal neurological disease in very early childhood. In this study, we report two siblings (21- and 8-year-old) affected by PCH1B with an unusual presentation. We identified compound heterozygosity for the well-established EXOSC3 variant c.395A > C, p.(Asp132Ala) and the novel variant c.572G > A, p.(Gly191Asp), expanding the genetic spectrum. Phenotypic presentation of the siblings was strikingly different from that of literature reports with a surprisingly mild disease manifestation and an unexpected intrafamilial variability. This study demonstrates the extensive clinical heterogeneity and the broad phenotypic spectrum associated with EXOSC3-associated disorders. Enlargement of sample sizes and reports of novel cases will be essential for the delineation of associated phenotypes.

Published
2019

41. Defining and expanding the phenotype of QARS-associated developmental epileptic encephalopathy

Author

Gareth Baynam, Christian Roth, Joseph Toulouse, Guido Rubboli, Karin Geleijns, Jonas Denecke, Robert Janowski, Dylan Gration, Diana Mitter, Alfred Peter Born, Dierk Niessing, Anne-Lise Poulat, Kimberly Nugent, Cathryn Poulton, Renzo Guerrini, Ghayda M. Mirzaa, Nicolas Chatron, Scott D. McLean, Eva H. Brilstra, H. Hjalgrim, Annalisa Vetro, Dorothée Ville, Rami Abou Jamra, Lauren Dreyer, Francesco Brancati, Katrine M Johannesen, Petra Muschke, Maja Hempel, Rikke S. Møller, Katherine L. Helbig, Gaetan Lesca, Anja Finck, Andrea Dieckmann, Tatjana Bierhals, E. Gardella, Andreas Merkenschlager, Solveig Schulz, and Johannes R. Lemke

Subjects
0303 health sciences, Pediatrics, medicine.medical_specialty, Progressive microcephaly, Microcephaly, business.industry, Genetic counseling, Encephalopathy, medicine.disease, Irritability, Short stature, Hypotonia, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, medicine, Neurology (clinical), medicine.symptom, business, 030217 neurology & neurosurgery, Genetics (clinical), 030304 developmental biology
Abstract

ObjectiveThe study is aimed at widening the clinical and genetic spectrum and at assessing genotype-phenotype associations in QARS encephalopathy.MethodsThrough diagnostic gene panel screening in an epilepsy cohort, and recruiting through GeneMatcher and our international network, we collected 10 patients with biallelic QARS variants. In addition, we collected data on 12 patients described in the literature to further delineate the associated phenotype in a total cohort of 22 patients. Computer modeling was used to assess changes on protein folding.ResultsBiallelic pathogenic variants in QARS cause a triad of progressive microcephaly, moderate to severe developmental delay, and early-onset epilepsy. Microcephaly was present at birth in 65%, and in all patients at follow-up. Moderate (14%) or severe (73%) developmental delay was characteristic, with no achievement of sitting (85%), walking (86%), or talking (90%). Additional features included irritability (91%), hypertonia/spasticity (75%), hypotonia (83%), stereotypic movements (75%), and short stature (56%). Seventy-nine percent had pharmacoresistant epilepsy with mainly neonatal onset. Characteristic cranial MRI findings include early-onset progressive atrophy of cerebral cortex (89%) and cerebellum (61%), enlargement of ventricles (95%), and age-dependent delayed myelination (88%). A small subset of patients displayed a less severe phenotype.ConclusionsThese data revealed first genotype-phenotype associations and may serve for improved interpretation of new QARS variants and well-founded genetic counseling.

Published
2019
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42. Bi-allelic Variants in METTL5 Cause Autosomal-Recessive Intellectual Disability and Microcephaly

Author

Daniel L. Polla, Zubair M. Ahmed, Minerva Contreras, Saima Riazuddin, Javed Akram, Dagmar Wieczorek, Muhammad Zaman Khan Assir, Thomas A. Blanpied, Elodie Richard, Hans van Bokhoven, Attia Razzaq, Sheikh Riazuddin, Moazzam N. Tarar, Asma A. Khan, Rami Abou Jamra, and Mohsin Shahzad

Subjects
0301 basic medicine, Adult, Male, Microcephaly, Protein family, Adolescent, In silico, Medizin, Genes, Recessive, Biology, Frameshift mutation, 03 medical and health sciences, 0302 clinical medicine, All institutes and research themes of the Radboud University Medical Center, Report, Intellectual Disability, Intellectual disability, Genetics, medicine, Humans, Allele, Zebrafish, Genetics (clinical), Exome sequencing, Alleles, Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Methyltransferases, medicine.disease, biology.organism_classification, Pedigree, 030104 developmental biology, Child, Preschool, Female, 030217 neurology & neurosurgery
Abstract

Intellectual disability (ID) is a genetically and clinically heterogeneous disorder, characterized by limited cognitive abilities and impaired adaptive behaviors. In recent years, exome sequencing (ES) has been instrumental in deciphering the genetic etiology of ID. Here, through ES of a large cohort of individuals with ID, we identified two bi-allelic frameshift variants in METTL5, c.344_345delGA (p.Arg115Asnfs(∗)19) and c.571_572delAA (p.Lys191Valfs(∗)10), in families of Pakistani and Yemenite origin. Both of these variants were segregating with moderate to severe ID, microcephaly, and various facial dysmorphisms, in an autosomal-recessive fashion. METTL5 is a member of the methyltransferase-like protein family, which encompasses proteins with a seven-beta-strand methyltransferase domain. We found METTL5 expression in various substructures of rodent and human brains and METTL5 protein to be enriched in the nucleus and synapses of the hippocampal neurons. Functional studies of these truncating variants in transiently transfected orthologous cells and cultured hippocampal rat neurons revealed no effect on the localization of METTL5 but alter its level of expression. Our in silico analysis and 3D modeling simulation predict disruption of METTL5 function by both variants. Finally, mettl5 knockdown in zebrafish resulted in microcephaly, recapitulating the human phenotype. This study provides evidence that biallelic variants in METTL5 cause ID and microcephaly in humans and highlights the essential role of METTL5 in brain development and neuronal function.

Published
2019

43. Heterozygous ANKRD17 loss of function variants cause a syndrome with intellectual disability, speech delay and dysmorphism

Author

Damien Smedley, Hailey Pinz, Chiara Kloechner, Grazia M.S. Mancini, Anna de Burca, Christopher T. Gordon, Emilia K. Bijlsma, Rebecca Wilaert, Jonas Denecke, Ingo Helbig, Nicola Brunetti-Pierri, Martina Wilke, Katta M. Girisha, Parmeet Kaur, Jeanne Amiel, Janette diMonda, Rolph Pfundt, Maya Chopra, Maria Arelin, Julie Evans, Hermine E. Veenstra-Knol, Micheil Innes, Kyra E. Stuurman, Janvier Porta Pelayo, Ugur Hodoglugil, Meriel McEntagart, Rosan Lechner, Anupriya Kaur, Sam Amin, Sarah E McKeown, Maja Hempel, Tjitske Kleefstra, Michelle L. Thompson, Tiffany Yip, Maggie Williams, Amelia Kirby, Jane Juusola, Anna Lehman, Gerarda Capuccio, Frank Sleutels, Rami Abou Jamra, Konrad Platzer, William A. Weiss, Martina Bebin, Jennifer Semotok, Stanislas Lyonnet, Naomi Yachelevich, Anni Niskakoski, Juanita Neira, Anne Slavotinek, Cacha Peters-Scholte, Usha Kini, Medard Hadonou, Mariëtte J.V. Hoffer, Anju Shukla, Sajel Lala, John Short, Susanne B. Kamphausen, Katherine L. Helbig, Sarah F. Smithson, Fanny Kortüm, Sandra Yang, Jill Clayton-Smith, Amy Whittle, and Alberto Fernández-Jaen

Subjects
medicine.medical_specialty, business.industry, Endocrinology, Diabetes and Metabolism, Audiology, medicine.disease, Biochemistry, Endocrinology, Speech delay, Intellectual disability, Genetics, Medicine, medicine.symptom, business, Molecular Biology, Loss function
Published
2021
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44. Broadening the phenotypic spectrum of pathogenic LARP7 variants: two cases with intellectual disability, variable growth retardation and distinct facial features

Author

Iris H.I.M. Hollink, Stella A. de Man, Aida M. Bertoli-Avella, Ingrid M.B.H. van de Laar, Majid Alfadhel, Anwar S Al-Wakeel, Farough Ababneh, Rami Abou Jamra, Arndt Rolfs, Rolph Pfundt, and Clinical Genetics

Subjects
Male, 0301 basic medicine, medicine.medical_specialty, Biology, Bioinformatics, Short stature, Frameshift mutation, 03 medical and health sciences, Intellectual Disability, Intellectual disability, Genetics, medicine, Humans, Child, Growth Disorders, Genetics (clinical), Neurodevelopmental disorders Donders Center for Medical Neuroscience [Radboudumc 7], Facies, medicine.disease, Stop codon, Human genetics, Phenotype, 030104 developmental biology, Ribonucleoproteins, Statistical genetics, Child, Preschool, Medical genetics, medicine.symptom, Primordial dwarfism
Abstract

Contains fulltext : 168335.pdf (Publisher’s version ) (Closed access) In 2012 Alazami et al. described a novel syndromic cause of primordial dwarfism with distinct facial features and severe intellectual disability. A homozygous frameshift mutation in LARP7, a chaperone of the noncoding RNA 7SK, was discovered in patients from a single consanguineous Saudi family. To date, only one additional patient has recently been described. To further delineate the phenotype associated with LARP7 mutations, we report two additional cases originating from the Netherlands and Saudi Arabia. The patients presented with intellectual disability, distinct facial features and variable short stature. We describe their clinical features and compare them with the previously reported patients. Both cases were identified by diagnostic whole-exome sequencing, which detected two homozygous pathogenic LARP7 variants: c.1091_1094delCGGT in the Dutch case and c.1045_1051dupAAGGATA in the Saudi Arabian case. Both variants are leading to frameshifts with introduction of premature stop codons, suggesting that loss of function is likely the disease mechanism. This study is an independent confirmation of the syndrome due to LARP7 depletion. Our cases broaden the associated clinical features of the syndrome and contribute to the delineation of the phenotypic spectrum of LARP7 mutations.

Published
2016
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45. Evolutionary conserved networks of human height identify multiple Mendelian causes of short stature

Author

Christian Thiel, H. G. Doerr, Christian Büttner, Martin Zenker, Christiane Zweier, Perundurai S. Dhandapany, Steffen Uebe, Carina Vogl, Heinrich Sticht, André Reis, Dagmar Wieczorek, Cornelia Kraus, Rami Abou Jamra, Alessandro De Luca, Anna Marie Jung, Leila Taher, Patrizia Klinger, Bernt Popp, Arif B. Ekici, Fulvia Ferrazzi, Anita Rauch, Tilman R. Rohrer, Erdmute Kunstmann, Antje Wiesener, and Nadine N. Hauer

Subjects
Male, Candidate gene, Multifactorial Inheritance, Population, Medizin, Dwarfism, Biology, Short stature, Article, 03 medical and health sciences, symbols.namesake, Exome Sequencing, Genetics, medicine, Humans, Exome, DNA sequencing, Human height, education, Child, Genetics (clinical), Exome sequencing, 0303 health sciences, education.field_of_study, Genetic counselling, Disease genetics, 030305 genetics & heredity, Infant, medicine.disease, Idiopathic short stature, Cytoskeletal Proteins, Child, Preschool, Mendelian inheritance, symbols, Female, medicine.symptom
Abstract

Height is a heritable and highly heterogeneous trait. Short stature affects 3% of the population and in most cases is genetic in origin. After excluding known causes, 67% of affected individuals remain without diagnosis. To identify novel candidate genes for short stature, we performed exome sequencing in 254 unrelated families with short stature of unknown cause and identified variants in 63 candidate genes in 92 (36%) independent families. Based on systematic characterization of variants and functional analysis including expression in chondrocytes, we classified 13 genes as strong candidates. Whereas variants in at least two families were detected for all 13 candidates, two genes had variants in 6 (UBR4) and 8 (LAMA5) families, respectively. To facilitate their characterization, we established a clustered network of 1025 known growth and short stature genes, which yielded 29 significantly enriched clusters, including skeletal system development, appendage development, metabolic processes, and ciliopathy. Eleven of the candidate genes mapped to 21 of these clusters, including CPZ, EDEM3, FBRS, IFT81, KCND1, PLXNA3, RASA3, SLC7A8, UBR4, USP45, and ZFHX3. Fifty additional growth-related candidates we identified await confirmation in other affected families. Our study identifies Mendelian forms of growth retardation as an important component of idiopathic short stature.

Published
2018

46. Next-generation sequencing of 32 genes associated with hereditary aortopathies and related disorders of connective tissue in a cohort of 199 patients

Author

Rixa Woitschach, Helke Schüler, Sara Sheikhzadeh, Jakob Olfe, Melanie J Hartmann, Alexandra Wey-Fabrizius, Christine Petersen, Alexander E Volk, Malik Alawi, Dagmar Wieczorek, Meike Rybczynski, Friederike Sophia Seggewies, Kerstin Kutsche, Isabella Rau, Diana Mitter, Georg Rosenberger, Veronika Stark, Margarete Koch-Hogrebe, Sina Renner, Yskert von Kodolitsch, Verena Kolbe, Christian Kubisch, Rami Abou Jamra, Maja Hempel, Thomas S. Mir, Guntram Borck, Janine Altmüller, Mathias Hillebrand, Katja Kloth, Adrian Mahlmann, and Elke Roser

Subjects
Genetics, Marfan syndrome, Adult, Male, Connective Tissue Disorder, High-Throughput Nucleotide Sequencing, Disease, Biology, Quantitative trait locus, medicine.disease, DNA sequencing, Marfan Syndrome, Cohort Studies, Connective Tissue, Cohort, medicine, Humans, Female, Genetic Testing, Connective Tissue Diseases, Gene, Genetics (clinical), Exome sequencing, Aorta, Biomarkers
Abstract

Heritable factors play an important etiologic role in connective tissue disorders (CTD) with vascular involvement, and a genetic diagnosis is getting increasingly important for gene-tailored, personalized patient management. We analyzed 32 disease-associated genes by using targeted next-generation sequencing and exome sequencing in a clinically relevant cohort of 199 individuals. We classified and refined sequence variants according to their likelihood for pathogenicity. We identified 1 pathogenic variant (PV; in FBN1 or SMAD3) in 15 patients (7.5%) and ≥1 likely pathogenic variant (LPV; in COL3A1, FBN1, FBN2, LOX, MYH11, SMAD3, TGFBR1, or TGFBR2) in 19 individuals (9.6%), together resulting in 17.1% diagnostic yield. Thirteen PV/LPV were novel. Of PV/LPV-negative patients 47 (23.6%) showed ≥1 variant of uncertain significance (VUS). Twenty-five patients had concomitant variants. In-depth evaluation of reported/calculated variant classes resulted in reclassification of 19.8% of variants. Variant classification and refinement are essential for shaping mutational spectra of disease genes, thereby improving clinical sensitivity. Obligate stringent multigene analysis is a powerful tool for identifying genetic causes of clinically related CTDs. Nonetheless, the relatively high rate of PV/LPV/VUS-negative patients underscores the existence of yet unknown disease loci and/or oligogenic/polygenic inheritance.

Published
2018

47. Value of renal gene panel diagnostics in adults waiting for kidney transplantation due to undetermined end-stage renal disease

Author

Rami Abou Jamra, Ria Schönauer, Timo Wagner, Anette Bachmann, Carsten Bergmann, Jan Halbritter, Johannes Münch, Tom H. Lindner, Julia Hentschel, Daniel Seehofer, Isabel Ottlewski, and Antje Weimann

Subjects
0301 basic medicine, Adult, Male, medicine.medical_specialty, Thrombotic microangiopathy, Adolescent, Waiting Lists, Biopsy, DNA Mutational Analysis, 030232 urology & nephrology, Autosomal dominant polycystic kidney disease, Context (language use), urologic and male genital diseases, Kidney, End stage renal disease, 03 medical and health sciences, 0302 clinical medicine, Focal segmental glomerulosclerosis, Internal medicine, medicine, Humans, Genetic Testing, Kidney transplantation, business.industry, Middle Aged, medicine.disease, Polycystic Kidney, Autosomal Dominant, Kidney Transplantation, Transplantation, 030104 developmental biology, Nephrology, Preoperative Period, Feasibility Studies, Kidney Failure, Chronic, Female, business, Nephrosclerosis, Biomarkers
Abstract

End-stage renal disease (ESRD) of undetermined etiology is highly prevalent and constitutes a significant clinical challenge, particularly in the context of kidney transplantation (KT). Despite the identification of numerous rare hereditary nephropathies over the last few decades, patients with undetermined ESRD are not being systematically investigated for rare genetic causes in clinical practice. To address this, we utilized mutation analysis in patients on the kidney transplant waitlist and scrutinized underlying renal diagnoses of 142 patients in a single center KT-waitlist. This cohort was stratified into 85 cases of determined and 57 cases of undetermined ESRD. The latter patients were analyzed by a renal gene panel for mutations in 209 genes associated with ESRD. The most likely genetic diagnoses in 12% of the tested individuals with undetermined ESRD were established. All of these patients showed mutations in genes encoding components of the glomerular filtration barrier. Taken together, hereditary nephropathies, including autosomal dominant polycystic kidney disease, were identified in 35 of the 142 patients of the waitlist cohort. By significantly increasing the proportion of hereditary diagnoses from 29 to 35 patients, the rate of undetermined ESRD significantly decreased from 57 to 51 patients. This study demonstrates the beneficial use of genetic diagnostics in significantly unraveling undetermined ESRD cases prior to KT. Thus, in the absence of renal histology or the presence of unspecific histological conditions, such as hypertensive nephrosclerosis, focal segmental glomerulosclerosis or thrombotic microangiopathy, genetic analysis may provide a robust and specific renal diagnosis and allow for optimizing pre- and post-KT management.

Published
2018

48. A new p.(Ile66Serfs*93) IGF2 variant is associated with pre- and postnatal growth retardation

Author

Wieland Kiess, Denise Rockstroh, Diana Le Duc, Johannes R. Lemke, Heike Pfäffle, Franziska Rößler, Franziska Schlensog-Schuster, Roland Pfäffle, Rami Abou Jamra, John T. Heiker, and Jürgen Kratzsch

Subjects
Male, medicine.medical_specialty, Endocrinology, Diabetes and Metabolism, Intrauterine growth restriction, 030209 endocrinology & metabolism, Biology, medicine.disease_cause, Fingers, 03 medical and health sciences, 0302 clinical medicine, Endocrinology, Insulin-Like Growth Factor II, Pregnancy, Internal medicine, medicine, Humans, Genetic Predisposition to Disease, Allele, Gene, PI3K/AKT/mTOR pathway, Growth Disorders, Insulin-like growth factor 1 receptor, Mutation, Fetal Growth Retardation, General Medicine, medicine.disease, Phenotype, Cleft Palate, Facial Asymmetry, 030220 oncology & carcinogenesis, Child, Preschool, Female, Genomic imprinting, Signal Transduction
Abstract

Objective The IGF/IGF1R axis is involved in the regulation of human growth. Both IGF1 and IGF2 can bind to the IGF1R in order to promote growth via the downstream PI3K/AKT pathway. Pathogenic mutations in IGF1 and IGF1R determine intrauterine growth restriction and affect postnatal body growth. However, to date, there are only few reports of pathogenic IGF2 mutations causing severe prenatal, as well as postnatal growth retardation. Results Here we describe a de novo c.195delC IGF2 variant (NM_000612, p.(Ile66Serfs*93)) in a 4-year-old patient with severe pre- and post-natal growth retardation in combination with dystrophy, facial dimorphism, finger deformities, as well as a patent ductus. Cloning and sequencing of a long-range PCR product harboring the deletion and a SNP informative site chr11:2153634 (rs680, NC_000011.9:g.2153634T>C) demonstrated that the variant resided on the paternal allele. This finding is consistent with the known maternal imprinting of IGF2. 3D protein structure prediction and overexpression studies demonstrated that the p.(Ile66Serfs*93) IGF2 gene variation resulted in an altered protein structure that impaired ligand/receptor binding and thus prevents IGF1R activation. Conclusion The severity of the phenotype in combination with the dominant mode of transmission provides further evidence for the involvement of IGF2 in growth disorders.

Published
2018

49. Biallelic loss of human CTNNA2, encoding alpha N-catenin, leads to ARP2/3 complex overactivity and disordered cortical neuronal migration

Author

Bülent Kara, Ariana Kariminejad, Elif Fenercioglu, Faruk Incecik, William B. Dobyns, Sumita Danda, Jamel Chelly, Rengang Wang, Hind Y. Al-Abdulwahed, Lobna Mansour, Nouriya Al-Sanaa, Hülya Kayserili, Martin W. Breuss, Jennifer L. Silhavy, Ahmet Okay Caglayan, Valentina Stanley, Kaya Bilguvar, Bruce A. Barshop, Tawfeg Ben-Omran, Gia Melikishvili, Rasim Ozgur Rosti, Rami Abou Jamra, Na Cai, Murat Gunel, Damir Musaev, Faezeh Mojahedi, Ashleigh E. Schaffer, Hisham Megahed, Eissa Faqeih, Rahul Nachnani, Cahide Yilmaz, Hande Kaymakçalan, Seham Elsharif, Biayna Sukhudyan, Brett Copeland, Joseph G. Gleeson, Ian Miller, Eric C. Scott, Maha S. Zaki, Majdi Kara, Aneesha Kalur, Kiely N. James, Seung Tae Baek, Yasemin Alanay, Çukurova Üniversitesi, and Acibadem University Dspace

Subjects
0301 basic medicine, Neurite, Arp2/3 complex, Nerve Tissue Proteins, macromolecular substances, Biology, medicine.disease_cause, Article, Actin-Related Protein 2-3 Complex, Mice, 03 medical and health sciences, alpha-catenin, 0302 clinical medicine, Cell Movement, Genetics, medicine, pachygyria, Animals, Humans, polarity, Psychological repression, Actin, Cerebral Cortex, Neurons, neuronal migration, Mutation, Genome, Human, primary neurite, Pachygyria, beta-catenin, Embryo, Mammalian, medicine.disease, Wnt signaling, Pedigree, 3. Good health, Cell biology, Mice, Inbred C57BL, actin remodeling, centrosome, 030104 developmental biology, medicine.anatomical_structure, Cerebral cortex, Catenin, biology.protein, Arp2/3, alpha Catenin, 030217 neurology & neurosurgery
Abstract

WOS: 000440423400008 PubMed ID: 30013181 Neuronal migration defects, including pachygyria, are among the most severe developmental brain defects in humans. Here, we identify biallelic truncating mutations in CTNNA2, encoding alpha N-catenin, in patients with a distinct recessive form of pachygyria. CTNNA2 was expressed in human cerebral cortex, and its loss in neurons led to defects in neurite stability and migration. The alpha N-catenin paralog, alpha E-catenin, acts as a switch regulating the balance between beta-catenin and Arp2/3 actin filament activities(1). Loss of alpha N-catenin did not affect beta-catenin signaling, but recombinant alpha N-catenin interacted with purified actin and repressed ARP2/3 actin-branching activity. The actin-binding domain of alpha N-catenin or ARP2/3 inhibitors rescued the neuronal phenotype associated with CTNNA2 loss, suggesting ARP2/3 de-repression as a potential disease mechanism. Our findings identify CTNNA2 as the first catenin family member with biallelic mutations in humans, causing a new pachygyria syndrome linked to actin regulation, and uncover a key factor involved in ARP2/3 repression in neurons. NIHUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R01NS041537, R01NS048453, R01NS052455, P01HD070494, P30NS047101]; Qatar National Research Fund [6-1463-351]; Simons Foundation Autism Research Initiative; Howard Hughes Medical InstituteHoward Hughes Medical Institute; A.P. Giannini Fellowship; NIH Pathway to Independence AwardUnited States Department of Health & Human ServicesNational Institutes of Health (NIH) - USA [R00HD082337]; 2014 NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation; Yale Center for Mendelian Disorders [UMIHG008900, UMIHG006504] We thank the patients and their families for participation. We thank A. Wynshaw-Boris for generous scientific and editorial input. The research was supported by NIH R01NS041537, R01NS048453, R01NS052455, P01HD070494, P30NS047101, Qatar National Research Fund number 6-1463-351, the Simons Foundation Autism Research Initiative, and the Howard Hughes Medical Institute (to J.G.G). A.E.S. is a recipient of an A.P. Giannini Fellowship and an NIH Pathway to Independence Award, R00HD082337. S.T.B. is supported by a 2014 NARSAD Young Investigator Grant from the Brain and Behavior Research Foundation. We thank the Broad Institute and Yale Center for Mendelian Disorders (UMIHG008900 to D. MacArthur and H. Rehm, and UMIHG006504 to R. Lifton and M.G.), and the Gregory M. Kiez and Mehmet Kutman Foundation (to M.G). We acknowledge M. Gerstein, S. Mane, A. B. Ekici, and S. Uebe for sequencing support and analysis, the Yale Biomedical High Performance Computing Center for data analysis and storage, the Yale Program on Neurogenetics, and the Yale Center for Human Genetics and Genomics. Exome data have been deposited into the database of Genotypes and Phenotypes (phs000288).

Published
2018

50. MAN1B1 Mutation Leads to a Recognizable Phenotype: A Case Report and Future Prospects

Author

Rami Abou Jamra, Jörg T. Epplen, André Reis, and Sabine Hoffjan

Subjects
Pediatrics, medicine.medical_specialty, business.industry, Genetic counseling, medicine.disease, Phenotype, Mutation (genetic algorithm), Intellectual disability, Genetics, medicine, Medical genetics, Truncal obesity, business, Congenital disorder of glycosylation, Genetics (clinical), Exome sequencing
Abstract

Intellectual disability (ID) is one of the most common reasons for referral to genetic counseling. Nevertheless, in over 50% of the cases no diagnosis can be made. Here, we present how exome sequencing in combination with medical genetics evaluation led to the identification of a known pathogenic homozygous mutation in MAN1B1 in a consanguineous Turkish family. The phenotype comprised mild ID, truncal obesity and facial dysmorphism, comparable to that of the patients in the 3 recent publications on mutations in this gene. Clinically, the majority of patients in the literature showed congenital disorder of glycosylation syndrome type 2. In this study, we summarize the current knowledge about MAN1B1 mutations from the literature as well as databases and suggest that exome sequencing should be implemented in a larger scale in routine diagnostics, since autosomal recessive ID has proven to be extremely heterogeneous. Even syndromic patterns may only become recognizable retrospectively.

Published
2015
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