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1. Exome copy number variant detection, analysis, and classification in a large cohort of families with undiagnosed rare genetic disease.

Author

Lemire, Gabrielle, Sanchis-Juan, Alba, Russell, Kathryn, Baxter, Samantha, Chao, Katherine, Singer-Berk, Moriel, Groopman, Emily, Wong, Isaac, England, Eleina, Goodrich, Julia, Pais, Lynn, Austin-Tse, Christina, DiTroia, Stephanie, OHeir, Emily, Ganesh, Vijay, Wojcik, Monica, Evangelista, Emily, Snow, Hana, Osei-Owusu, Ikeoluwa, Fu, Jack, Singh, Mugdha, Mostovoy, Yulia, Huang, Steve, Garimella, Kiran, Kirkham, Samantha, Neil, Jennifer, Shao, Diane, Walsh, Christopher, Argilli, Emanuela, Le, Carolyn, Sherr, Elliott, Gleeson, Joseph, Shril, Shirlee, Schneider, Ronen, Hildebrandt, Friedhelm, Sankaran, Vijay, Madden, Jill, Genetti, Casie, Beggs, Alan, Agrawal, Pankaj, Bujakowska, Kinga, Place, Emily, Pierce, Eric, Donkervoort, Sandra, Bönnemann, Carsten, Gallacher, Lyndon, Stark, Zornitza, Tan, Tiong, White, Susan, Töpf, Ana, Straub, Volker, Fleming, Mark, Pollak, Martin, Õunap, Katrin, Pajusalu, Sander, Donald, Kirsten, Bruwer, Zandre, Ravenscroft, Gianina, Laing, Nigel, MacArthur, Daniel, Rehm, Heidi, Talkowski, Michael, Brand, Harrison, and ODonnell-Luria, Anne

Subjects
CNV, GATK-gCNV, copy number variant, diagnostic yield, exome, variant classification, Humans, DNA Copy Number Variations, Rare Diseases, Exome, Male, Female, Exome Sequencing, Cohort Studies, Genetic Testing
Abstract

Copy number variants (CNVs) are significant contributors to the pathogenicity of rare genetic diseases and, with new innovative methods, can now reliably be identified from exome sequencing. Challenges still remain in accurate classification of CNV pathogenicity. CNV calling using GATK-gCNV was performed on exomes from a cohort of 6,633 families (15,759 individuals) with heterogeneous phenotypes and variable prior genetic testing collected at the Broad Institute Center for Mendelian Genomics of the Genomics Research to Elucidate the Genetics of Rare Diseases consortium and analyzed using the seqr platform. The addition of CNV detection to exome analysis identified causal CNVs for 171 families (2.6%). The estimated sizes of CNVs ranged from 293 bp to 80 Mb. The causal CNVs consisted of 140 deletions, 15 duplications, 3 suspected complex structural variants (SVs), 3 insertions, and 10 complex SVs, the latter two groups being identified by orthogonal confirmation methods. To classify CNV variant pathogenicity, we used the 2020 American College of Medical Genetics and Genomics/ClinGen CNV interpretation standards and developed additional criteria to evaluate allelic and functional data as well as variants on the X chromosome to further advance the framework. We interpreted 151 CNVs as likely pathogenic/pathogenic and 20 CNVs as high-interest variants of uncertain significance. Calling CNVs from existing exome data increases the diagnostic yield for individuals undiagnosed after standard testing approaches, providing a higher-resolution alternative to arrays at a fraction of the cost of genome sequencing. Our improvements to the classification approach advances the systematic framework to assess the pathogenicity of CNVs.

Published
2024

2. Recurring homozygous ACTN2 variant (p.Arg506Gly) causes a recessive myopathy.

Author

Donkervoort, Sandra, Mohassel, Payam, OLeary, Melanie, Bonner, Devon, Hartley, Taila, Acquaye, Nicole, Brull, Astrid, Saporta, Mario, Dyment, David, Sampson, Jacinda, Pajusalu, Sander, Austin-Tse, Christina, Hurth, Kyle, Cohen, Julie, McWalter, Kirsty, Warman-Chardon, Jodi, Crunk, Amy, Foley, A, Mammen, Andrew, Wheeler, Matthew, ODonnell-Luria, Anne, Bönnemann, Carsten, and Mozaffar, Tahseen

Subjects
Adult, Humans, Muscular Diseases, Muscle, Skeletal, Actinin, Phenotype, Cardiomyopathies
Abstract

OBJECTIVE: ACTN2, encoding alpha-actinin-2, is essential for cardiac and skeletal muscle sarcomeric function. ACTN2 variants are a known cause of cardiomyopathy without skeletal muscle involvement. Recently, specific dominant monoallelic variants were reported as a rare cause of core myopathy of variable clinical onset, although the pathomechanism remains to be elucidated. The possibility of a recessively inherited ACTN2-myopathy has also been proposed in a single series. METHODS: We provide clinical, imaging, and histological characterization of a series of patients with a novel biallelic ACTN2 variant. RESULTS: We report seven patients from five families with a recurring biallelic variant in ACTN2: c.1516A>G (p.Arg506Gly), all manifesting with a consistent phenotype of asymmetric, progressive, proximal, and distal lower extremity predominant muscle weakness. None of the patients have cardiomyopathy or respiratory insufficiency. Notably, all patients report Palestinian ethnicity, suggesting a possible founder ACTN2 variant, which was confirmed through haplotype analysis in two families. Muscle biopsies reveal an underlying myopathic process with disruption of the intermyofibrillar architecture, Type I fiber predominance and atrophy. MRI of the lower extremities demonstrate a distinct pattern of asymmetric muscle involvement with selective involvement of the hamstrings and adductors in the thigh, and anterior tibial group and soleus in the lower leg. Using an in vitro splicing assay, we show that c.1516A>G ACTN2 does not impair normal splicing. INTERPRETATION: This series further establishes ACTN2 as a muscle disease gene, now also including variants with a recessive inheritance mode, and expands the clinical spectrum of actinopathies to adult-onset progressive muscle disease.

Published
2024

3. Diagnosing missed cases of spinal muscular atrophy in genome, exome, and panel sequencing data sets

Author

Weisburd, Ben, Sharma, Rakshya, Pata, Villem, Reimand, Tiia, Ganesh, Vijay S., Austin-Tse, Christina, Osei-Owusu, Ikeoluwa, O’Heir, Emily, O’Leary, Melanie, Pais, Lynn, Stafki, Seth A., Daugherty, Audrey L., Folland, Chiara, Perić, Stojan, Fahmy, Nagia, Udd, Bjarne, Horakova, Magda, Łusakowska, Anna, Manoj, Rajanna, Nalini, Atchayaram, Karcagi, Veronika, Polavarapu, Kiran, Lochmüller, Hanns, Horvath, Rita, Bönnemann, Carsten G., Donkervoort, Sandra, Haliloğlu, Göknur, Herguner, Ozlem, Kang, Peter B., Ravenscroft, Gianina, Laing, Nigel, Scott, Hamish S., Töpf, Ana, Straub, Volker, Pajusalu, Sander, Õunap, Katrin, Tiao, Grace, Rehm, Heidi L., and O’Donnell-Luria, Anne

Published
2024
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4. Truncating SRCAP variants outside the Floating-Harbor syndrome locus cause a distinct neurodevelopmental disorder with a specific DNA methylation signature

Author

Rots, Dmitrijs, Chater-Diehl, Eric, Dingemans, Alexander JM, Goodman, Sarah J, Siu, Michelle T, Cytrynbaum, Cheryl, Choufani, Sanaa, Hoang, Ny, Walker, Susan, Awamleh, Zain, Charkow, Joshua, Meyn, Stephen, Pfundt, Rolph, Rinne, Tuula, Gardeitchik, Thatjana, de Vries, Bert BA, Deden, A Chantal, Leenders, Erika, Kwint, Michael, Stumpel, Constance TRM, Stevens, Servi JC, Vermeulen, Jeroen R, van Harssel, Jeske VT, Bosch, Danielle GM, van Gassen, Koen LI, van Binsbergen, Ellen, de Geus, Christa M, Brackel, Hein, Hempel, Maja, Lessel, Davor, Denecke, Jonas, Slavotinek, Anne, Strober, Jonathan, Crunk, Amy, Folk, Leandra, Wentzensen, Ingrid M, Yang, Hui, Zou, Fanggeng, Millan, Francisca, Person, Richard, Xie, Yili, Liu, Shuxi, Ousager, Lilian B, Larsen, Martin, Schultz-Rogers, Laura, Morava, Eva, Klee, Eric W, Berry, Ian R, Campbell, Jennifer, Lindstrom, Kristin, Pruniski, Brianna, Neumeyer, Ann M, Radley, Jessica A, Phornphutkul, Chanika, Schmidt, Berkley, Wilson, William G, Õunap, Katrin, Reinson, Karit, Pajusalu, Sander, van Haeringen, Arie, Ruivenkamp, Claudia, Cuperus, Roos, Santos-Simarro, Fernando, Palomares-Bralo, María, Pacio-Míguez, Marta, Ritter, Alyssa, Bhoj, Elizabeth, Tønne, Elin, Tveten, Kristian, Cappuccio, Gerarda, Brunetti-Pierri, Nicola, Rowe, Leah, Bunn, Jason, Saenz, Margarita, Platzer, Konrad, Mertens, Mareike, Caluseriu, Oana, Nowaczyk, Małgorzata JM, Cohn, Ronald D, Kannu, Peter, Alkhunaizi, Ebba, Chitayat, David, Scherer, Stephen W, Brunner, Han G, Vissers, Lisenka ELM, Kleefstra, Tjitske, Koolen, David A, and Weksberg, Rosanna

Subjects
Genetics, Clinical Research, Brain Disorders, Mental Health, Intellectual and Developmental Disabilities (IDD), Aetiology, 2.1 Biological and endogenous factors, Abnormalities, Multiple, Adenosine Triphosphatases, Case-Control Studies, Cohort Studies, Craniofacial Abnormalities, DNA Methylation, Epigenesis, Genetic, Female, Genetic Predisposition to Disease, Growth Disorders, Heart Septal Defects, Ventricular, Humans, Infant, Newborn, Male, Mutation, Neurodevelopmental Disorders, Phenotype, DNA methylation signature, Floating-Harbor syndrome, SRCAP, epigenomics, genotype-phenotype correlation, intellectual disability, neurodevelopmental disorders, non-FLHS SRCAP-related NDD, nonsense-mediated decay, speech delay, Biological Sciences, Medical and Health Sciences, Genetics & Heredity
Abstract

Truncating variants in exons 33 and 34 of the SNF2-related CREBBP activator protein (SRCAP) gene cause the neurodevelopmental disorder (NDD) Floating-Harbor syndrome (FLHS), characterized by short stature, speech delay, and facial dysmorphism. Here, we present a cohort of 33 individuals with clinical features distinct from FLHS and truncating (mostly de novo) SRCAP variants either proximal (n = 28) or distal (n = 5) to the FLHS locus. Detailed clinical characterization of the proximal SRCAP individuals identified shared characteristics: developmental delay with or without intellectual disability, behavioral and psychiatric problems, non-specific facial features, musculoskeletal issues, and hypotonia. Because FLHS is known to be associated with a unique set of DNA methylation (DNAm) changes in blood, a DNAm signature, we investigated whether there was a distinct signature associated with our affected individuals. A machine-learning model, based on the FLHS DNAm signature, negatively classified all our tested subjects. Comparing proximal variants with typically developing controls, we identified a DNAm signature distinct from the FLHS signature. Based on the DNAm and clinical data, we refer to the condition as "non-FLHS SRCAP-related NDD." All five distal variants classified negatively using the FLHS DNAm model while two classified positively using the proximal model. This suggests divergent pathogenicity of these variants, though clinically the distal group presented with NDD, similar to the proximal SRCAP group. In summary, for SRCAP, there is a clear relationship between variant location, DNAm profile, and clinical phenotype. These results highlight the power of combined epigenetic, molecular, and clinical studies to identify and characterize genotype-epigenotype-phenotype correlations.

Published
2021

5. Linkage-specific deubiquitylation by OTUD5 defines an embryonic pathway intolerant to genomic variation

Author

Beck, David B, Basar, Mohammed A, Asmar, Anthony J, Thompson, Joyce J, Oda, Hirotsugu, Uehara, Daniela T, Saida, Ken, Pajusalu, Sander, Talvik, Inga, D’Souza, Precilla, Bodurtha, Joann, Mu, Weiyi, Barañano, Kristin W, Miyake, Noriko, Wang, Raymond, Kempers, Marlies, Tamada, Tomoko, Nishimura, Yutaka, Okada, Satoshi, Kosho, Tomoki, Dale, Ryan, Mitra, Apratim, Macnamara, Ellen, Matsumoto, Naomichi, Inazawa, Johji, Walkiewicz, Magdalena, Õunap, Katrin, Tifft, Cynthia J, Aksentijevich, Ivona, Kastner, Daniel L, Rocha, Pedro P, and Werner, Achim

Subjects
Biochemistry and Cell Biology, Biomedical and Clinical Sciences, Genetics, Biological Sciences, Human Genome, Rare Diseases, Pediatric, Generic health relevance, Chromatin, Genomics, Humans, Signal Transduction, Ubiquitin, Ubiquitination, Undiagnosed Diseases Network
Abstract

Reversible modification of proteins with linkage-specific ubiquitin chains is critical for intracellular signaling. Information on physiological roles and underlying mechanisms of particular ubiquitin linkages during human development are limited. Here, relying on genomic constraint scores, we identify 10 patients with multiple congenital anomalies caused by hemizygous variants in OTUD5, encoding a K48/K63 linkage-specific deubiquitylase. By studying these mutations, we find that OTUD5 controls neuroectodermal differentiation through cleaving K48-linked ubiquitin chains to counteract degradation of select chromatin regulators (e.g., ARID1A/B, histone deacetylase 2, and HCF1), mutations of which underlie diseases that exhibit phenotypic overlap with OTUD5 patients. Loss of OTUD5 during differentiation leads to less accessible chromatin at neuroectodermal enhancers and aberrant gene expression. Our study describes a previously unidentified disorder we name LINKED (LINKage-specific deubiquitylation deficiency-induced Embryonic Defects) syndrome and reveals linkage-specific ubiquitin cleavage from chromatin remodelers as an essential signaling mode that coordinates chromatin remodeling during embryogenesis.

Published
2021

6. Dual Molecular Effects of Dominant RORA Mutations Cause Two Variants of Syndromic Intellectual Disability with Either Autism or Cerebellar Ataxia

Author

Guissart, Claire, Latypova, Xenia, Rollier, Paul, Khan, Tahir N, Stamberger, Hannah, McWalter, Kirsty, Cho, Megan T, Kjaergaard, Susanne, Weckhuysen, Sarah, Lesca, Gaetan, Besnard, Thomas, Õunap, Katrin, Schema, Lynn, Chiocchetti, Andreas G, McDonald, Marie, de Bellescize, Julitta, Vincent, Marie, Van Esch, Hilde, Sattler, Shannon, Forghani, Irman, Thiffault, Isabelle, Freitag, Christine M, Barbouth, Deborah Sara, Cadieux-Dion, Maxime, Willaert, Rebecca, Sacoto, Maria J Guillen, Safina, Nicole P, Dubourg, Christèle, Grote, Lauren, Carré, Wilfrid, Saunders, Carol, Pajusalu, Sander, Farrow, Emily, Boland, Anne, Karlowicz, Danielle Hays, Deleuze, Jean-François, Wojcik, Monica H, Pressman, Rena, Isidor, Bertrand, Vogels, Annick, Van Paesschen, Wim, Al-Gazali, Lihadh, Shamsi, Aisha Mohamed Al, Claustres, Mireille, Pujol, Aurora, Sanders, Stephan J, Rivier, François, Leboucq, Nicolas, Cogné, Benjamin, Sasorith, Souphatta, Sanlaville, Damien, Retterer, Kyle, Odent, Sylvie, Katsanis, Nicholas, Bézieau, Stéphane, Koenig, Michel, Davis, Erica E, Pasquier, Laurent, and Küry, Sébastien

Subjects
Biological Sciences, Bioinformatics and Computational Biology, Biomedical and Clinical Sciences, Genetics, Intellectual and Developmental Disabilities (IDD), Neurodegenerative, Neurosciences, Pediatric, Rare Diseases, Brain Disorders, Autism, Mental Health, 2.1 Biological and endogenous factors, Aetiology, Neurological, Adolescent, Adult, Aged, 80 and over, Alleles, Animals, Autistic Disorder, Brain, Cerebellar Ataxia, Child, Child, Preschool, DNA Copy Number Variations, Disease Models, Animal, Female, Genes, Dominant, Genetic Complementation Test, Humans, Intellectual Disability, Larva, Magnetic Resonance Imaging, Male, Middle Aged, Mutation, Missense, Nuclear Receptor Subfamily 1, Group F, Member 1, Purkinje Cells, Syndrome, Zebrafish, RORA, autistic features, cerebellar ataxia, dual molecular effects, epilepsy, intellectual disability, neurodevelopmental disorder, Medical and Health Sciences, Genetics & Heredity, Biological sciences, Biomedical and clinical sciences, Health sciences
Abstract

RORα, the RAR-related orphan nuclear receptor alpha, is essential for cerebellar development. The spontaneous mutant mouse staggerer, with an ataxic gait caused by neurodegeneration of cerebellar Purkinje cells, was discovered two decades ago to result from homozygous intragenic Rora deletions. However, RORA mutations were hitherto undocumented in humans. Through a multi-centric collaboration, we identified three copy-number variant deletions (two de novo and one dominantly inherited in three generations), one de novo disrupting duplication, and nine de novo point mutations (three truncating, one canonical splice site, and five missense mutations) involving RORA in 16 individuals from 13 families with variable neurodevelopmental delay and intellectual disability (ID)-associated autistic features, cerebellar ataxia, and epilepsy. Consistent with the human and mouse data, disruption of the D. rerio ortholog, roraa, causes significant reduction in the size of the developing cerebellum. Systematic in vivo complementation studies showed that, whereas wild-type human RORA mRNA could complement the cerebellar pathology, missense variants had two distinct pathogenic mechanisms of either haploinsufficiency or a dominant toxic effect according to their localization in the ligand-binding or DNA-binding domains, respectively. This dichotomous direction of effect is likely relevant to the phenotype in humans: individuals with loss-of-function variants leading to haploinsufficiency show ID with autistic features, while individuals with de novo dominant toxic variants present with ID, ataxia, and cerebellar atrophy. Our combined genetic and functional data highlight the complex mutational landscape at the human RORA locus and suggest that dual mutational effects likely determine phenotypic outcome.

Published
2018

7. Clustered mutations in the GRIK2 kainate receptor subunit gene underlie diverse neurodevelopmental disorders

Author

Stolz, Jacob R., Foote, Kendall M., Veenstra-Knol, Hermine E., Pfundt, Rolph, ten Broeke, Sanne W., de Leeuw, Nicole, Roht, Laura, Pajusalu, Sander, Part, Reelika, Rebane, Ionella, Õunap, Katrin, Stark, Zornitza, Kirk, Edwin P., Lawson, John A., Lunke, Sebastian, Christodoulou, John, Louie, Raymond J., Rogers, R. Curtis, Davis, Jessica M., Innes, A. Micheil, Wei, Xing-Chang, Keren, Boris, Mignot, Cyril, Lebel, Robert Roger, Sperber, Steven M., Sakonju, Ai, Dosa, Nienke, Barge-Schaapveld, Daniela Q.C.M., Peeters-Scholte, Cacha M.P.C.D., Ruivenkamp, Claudia A.L., van Bon, Bregje W., Kennedy, Joanna, Low, Karen J., Ellard, Sian, Pang, Lewis, Junewick, Joseph J., Mark, Paul R., Carvill, Gemma L., and Swanson, Geoffrey T.

Published
2021
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8. A form of muscular dystrophy associated with pathogenic variants in JAG2

Author

Coppens, Sandra, Barnard, Alison M., Puusepp, Sanna, Pajusalu, Sander, Õunap, Katrin, Vargas-Franco, Dorianmarie, Bruels, Christine C., Donkervoort, Sandra, Pais, Lynn, Chao, Katherine R., Goodrich, Julia K., England, Eleina M., Weisburd, Ben, Ganesh, Vijay S., Gudmundsson, Sanna, O’Donnell-Luria, Anne, Nigul, Mait, Ilves, Pilvi, Mohassel, Payam, Siddique, Teepu, Milone, Margherita, Nicolau, Stefan, Maroofian, Reza, Houlden, Henry, Hanna, Michael G., Quinlivan, Ros, Beiraghi Toosi, Mehran, Ghayoor Karimiani, Ehsan, Costagliola, Sabine, Deconinck, Nicolas, Kadhim, Hazim, Macke, Erica, Lanpher, Brendan C., Klee, Eric W., Łusakowska, Anna, Kostera-Pruszczyk, Anna, Hahn, Andreas, Schrank, Bertold, Nishino, Ichizo, Ogasawara, Masashi, El Sherif, Rasha, Stojkovic, Tanya, Nelson, Isabelle, Bonne, Gisèle, Cohen, Enzo, Boland-Augé, Anne, Deleuze, Jean-François, Meng, Yao, Töpf, Ana, Vilain, Catheline, Pacak, Christina A., Rivera-Zengotita, Marie L., Bönnemann, Carsten G., Straub, Volker, Handford, Penny A., Draper, Isabelle, Walter, Glenn A., and Kang, Peter B.

Published
2021
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9. Impaired protein hydroxylase activity causes replication stress and developmental abnormalities in humans

Author

Fletcher, Sally C., Hall, Charlotte, Kennedy, Tristan J., Pajusalu, Sander, Wojcik, Monica H., Boora, Uncaar, Li, Chan, Oja, Kaisa Teele, Hendrix, Eline, Westrip, Christian A.E., Andrijes, Regina, Piasecka, Sonia K., Singh, Mansi, Asrag, Mohammed E. El-, Ptasinska, Anetta, Tillmann, Vallo, Higgs, Martin R., Carere, Deanna A., Beggs, Andrew D., Pappas, John, Rabin, Rachel, Smerdon, Stephen J., Stewart, Grant S., Ounap, Katrin, and Coleman, Mathew L.

Subjects
Analysis, Hydroxylases -- Analysis, Embryonic development -- Analysis, Proteins -- Analysis
Abstract

Introduction The enzymatic incorporation of a single oxygen atom into an amino acid side chain is a relatively poorly characterized but emerging posttranslational modification (PTM) (1). Seminal work on the [...], Although protein hydroxylation is a relatively poorly characterized posttranslational modification, it has received significant recent attention following seminal work uncovering its role in oxygen sensing and hypoxia biology. Although the fundamental importance of protein hydroxylases in biology is becoming clear, the biochemical targets and cellular functions often remain enigmatic. JMJD5 is a "JmjC-only" protein hydroxylase that is essential for murine embryonic development and viability. However, no germline variants in JmjC-only hydroxylases, including JMJD5, have yet been described that are associated with any human pathology. Here we demonstrate that biallelic germline JMJD5 pathogenic variants are deleterious to JMJD5 mRNA splicing, protein stability, and hydroxylase activity, resulting in a human developmental disorder characterized by severe failure to thrive, intellectual disability, and facial dysmorphism. We show that the underlying cellular phenotype is associated with increased DNA replication stress and that this is critically dependent on the protein hydroxylase activity of JMJD5. This work contributes to our growing understanding of the role and importance of protein hydroxylases in human development and disease.

Published
2023
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10. Genotype/Phenotype Relationship: Lessons From 137 Patients With PMM2‐CDG.

Author

Pajusalu, Sander, Vals, Mari-Anne, Serrano, Mercedes, Witters, Peter, Cechova, Anna, Honzik, Tomáš, Edmondson, Andrew C., Ficicioglu, Can, Barone, Rita, De Lonlay, Pascale, Bérat, Claire-Marine, Vuillaumier-Barrot, Sandrine, Lam, Christina, Patterson, Marc C., Janssen, Mirian C. H., Martins, Esmeralda, Quelhas, Dulce, Sykut-Cegielska, Jolanta, Mousa, Jehan, and Urreizti, Roser

Abstract

We report on the largest single dataset of patients with PMM2‐CDG enrolled in an ongoing international, multicenter natural history study collecting genetic, clinical, and biological information to evaluate similarities with previous studies, report on novel findings, and, additionally, examine potential genotype/phenotype correlations. A total of 137 participants had complete genotype information, representing 60 unique variants, of which the most common were found to be p.Arg141His in 58.4% (n = 80) of participants, followed by p.Pro113Leu (21.2%, n = 29), and p.Phe119Leu (12.4%, n = 17), consistent with previous studies. Interestingly, six new variants were reported, comprised of five missense variants (p.Pro20Leu, p.Tyr64Ser, p.Phe68Cys, p.Tyr76His, and p.Arg238His) and one frameshift (c.696del p.Ala233Argfs∗100). Patient phenotypes were characterized via the Nijmegen Progression CDG Rating Scale (NPCRS), together with biochemical parameters, the most consistently dysregulated of which were coagulation factors, specifically antithrombin (below normal in 79.5%, 93 of 117), in addition to Factor XI and protein C activity. Patient genotypes were classified based upon the predicted pathogenetic mechanism of disease‐associated mutations, of which most were found in the catalysis/activation, folding, or dimerization regions of the PMM2 enzyme. Two different approaches were used to uncover genotype/phenotype relationships. The first characterized genotype only by the predicted pathogenic mechanisms and uncovered associated changes in biochemical parameters, not apparent using only NPCRS, involving catalysis/activation, dimerization, folding, and no protein variants. The second approach characterized genotype by the predicted pathogenic mechanism and/or individual variants when paired with a subset of severe nonfunctioning variants and uncovered correlations with both NPCRS and biochemical parameters, demonstrating that p.Cys241Ser was associated with milder disease, while p.Val231Met, dimerization, and folding variants with more severe disease. Although determining comprehensive genotype/phenotype relationships has previously proven challenging for PMM2‐CDG, the larger sample size, plus inclusion of biochemical parameters in the current study, has provided new insights into the interplay of genetics with disease. Trial Registration:NCT03173300. [ABSTRACT FROM AUTHOR]

Published
2024
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11. Monogenic variants in dystonia: an exome-wide sequencing study

Author

Zech, Michael, Jech, Robert, Boesch, Sylvia, Škorvánek, Matej, Weber, Sandrina, Wagner, Matias, Zhao, Chen, Jochim, Angela, Necpál, Ján, Dincer, Yasemin, Vill, Katharina, Distelmaier, Felix, Stoklosa, Malgorzata, Krenn, Martin, Grunwald, Stephan, Bock-Bierbaum, Tobias, Fečíková, Anna, Havránková, Petra, Roth, Jan, Příhodová, Iva, Adamovičová, Miriam, Ulmanová, Olga, Bechyně, Karel, Danhofer, Pavlína, Veselý, Branislav, Haň, Vladimír, Pavelekova, Petra, Gdovinová, Zuzana, Mantel, Tobias, Meindl, Tobias, Sitzberger, Alexandra, Schröder, Sebastian, Blaschek, Astrid, Roser, Timo, Bonfert, Michaela V, Haberlandt, Edda, Plecko, Barbara, Leineweber, Birgit, Berweck, Steffen, Herberhold, Thomas, Langguth, Berthold, Švantnerová, Jana, Minár, Michal, Ramos-Rivera, Gonzalo Alonso, Wojcik, Monica H, Pajusalu, Sander, Õunap, Katrin, Schatz, Ulrich A, Pölsler, Laura, Milenkovic, Ivan, Laccone, Franco, Pilshofer, Veronika, Colombo, Roberto, Patzer, Steffi, Iuso, Arcangela, Vera, Julia, Troncoso, Monica, Fang, Fang, Prokisch, Holger, Wilbert, Friederike, Eckenweiler, Matthias, Graf, Elisabeth, Westphal, Dominik S, Riedhammer, Korbinian M, Brunet, Theresa, Alhaddad, Bader, Berutti, Riccardo, Strom, Tim M, Hecht, Martin, Baumann, Matthias, Wolf, Marc, Telegrafi, Aida, Person, Richard E, Zamora, Francisca Millan, Henderson, Lindsay B, Weise, David, Musacchio, Thomas, Volkmann, Jens, Szuto, Anna, Becker, Jessica, Cremer, Kirsten, Sycha, Thomas, Zimprich, Fritz, Kraus, Verena, Makowski, Christine, Gonzalez-Alegre, Pedro, Bardakjian, Tanya M, Ozelius, Laurie J, Vetro, Annalisa, Guerrini, Renzo, Maier, Esther, Borggraefe, Ingo, Kuster, Alice, Wortmann, Saskia B, Hackenberg, Annette, Steinfeld, Robert, Assmann, Birgit, Staufner, Christian, Opladen, Thomas, Růžička, Evžen, Cohn, Ronald D, Dyment, David, Chung, Wendy K, Engels, Hartmut, Ceballos-Baumann, Andres, Ploski, Rafal, Daumke, Oliver, Haslinger, Bernhard, Mall, Volker, Oexle, Konrad, and Winkelmann, Juliane

Published
2020
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12. Genome Sequencing for Diagnosing Rare Diseases

Author

Wojcik, Monica H., primary, Lemire, Gabrielle, additional, Berger, Eva, additional, Zaki, Maha S., additional, Wissmann, Mariel, additional, Win, Wathone, additional, White, Susan M., additional, Weisburd, Ben, additional, Wieczorek, Dagmar, additional, Waddell, Leigh B., additional, Verboon, Jeffrey M., additional, VanNoy, Grace E., additional, Töpf, Ana, additional, Tan, Tiong Yang, additional, Syrbe, Steffen, additional, Strehlow, Vincent, additional, Straub, Volker, additional, Stenton, Sarah L., additional, Snow, Hana, additional, Singer-Berk, Moriel, additional, Silver, Josh, additional, Shril, Shirlee, additional, Seaby, Eleanor G., additional, Schneider, Ronen, additional, Sankaran, Vijay G., additional, Sanchis-Juan, Alba, additional, Russell, Kathryn A., additional, Reinson, Karit, additional, Ravenscroft, Gianina, additional, Radtke, Maximilian, additional, Popp, Denny, additional, Polster, Tilman, additional, Platzer, Konrad, additional, Pierce, Eric A., additional, Place, Emily M., additional, Pajusalu, Sander, additional, Pais, Lynn, additional, Õunap, Katrin, additional, Osei-Owusu, Ikeoluwa, additional, Opperman, Henry, additional, Okur, Volkan, additional, Oja, Kaisa Teele, additional, O’Leary, Melanie, additional, O’Heir, Emily, additional, Morel, Chantal F., additional, Merkenschlager, Andreas, additional, Marchant, Rhett G., additional, Mangilog, Brian E., additional, Madden, Jill A., additional, MacArthur, Daniel, additional, Lovgren, Alysia, additional, Lerner-Ellis, Jordan P., additional, Lin, Jasmine, additional, Laing, Nigel, additional, Hildebrandt, Friedhelm, additional, Hentschel, Julia, additional, Groopman, Emily, additional, Goodrich, Julia, additional, Gleeson, Joseph G., additional, Ghaoui, Roula, additional, Genetti, Casie A., additional, Gburek-Augustat, Janina, additional, Gazda, Hanna T., additional, Ganesh, Vijay S., additional, Ganapathi, Mythily, additional, Gallacher, Lyndon, additional, Fu, Jack M., additional, Evangelista, Emily, additional, England, Eleina, additional, Donkervoort, Sandra, additional, DiTroia, Stephanie, additional, Cooper, Sandra T., additional, Chung, Wendy K., additional, Christodoulou, John, additional, Chao, Katherine R., additional, Cato, Liam D., additional, Bujakowska, Kinga M., additional, Bryen, Samantha J., additional, Brand, Harrison, additional, Bönnemann, Carsten G., additional, Beggs, Alan H., additional, Baxter, Samantha M., additional, Bartolomaeus, Tobias, additional, Agrawal, Pankaj B., additional, Talkowski, Michael, additional, Austin-Tse, Christina, additional, Abou Jamra, Rami, additional, Rehm, Heidi L., additional, and O’Donnell-Luria, Anne, additional

Published
2024
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13. The phenotypic spectrum of PTCD3 deficiency

Author

Lace, Baiba, primary, Faqeih, Eissa, additional, Kaya, Namik, additional, Krumina, Zita, additional, Mayr, Johannes A., additional, Micule, Ieva, additional, Wright, Nathan Thompson, additional, Achleitner, Melanie T., additional, AlQudairy, Hanan, additional, Pajusalu, Sander, additional, Stavusis, Janis, additional, Zayakin, Pawel, additional, and Inashkina, Inna, additional

Published
2024
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15. CTCF variants in 39 individuals with a variable neurodevelopmental disorder broaden the mutational and clinical spectrum

Author

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

Published
2019
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18. Aberrant Function of the C-Terminal Tail of HIST1H1E Accelerates Cellular Senescence and Causes Premature Aging

Author

Flex, Elisabetta, Martinelli, Simone, Van Dijck, Anke, Ciolfi, Andrea, Cecchetti, Serena, Coluzzi, Elisa, Pannone, Luca, Andreoli, Cristina, Radio, Francesca Clementina, Pizzi, Simone, Carpentieri, Giovanna, Bruselles, Alessandro, Catanzaro, Giuseppina, Pedace, Lucia, Miele, Evelina, Carcarino, Elena, Ge, Xiaoyan, Chijiwa, Chieko, Lewis, M.E. Suzanne, Meuwissen, Marije, Kenis, Sandra, Van der Aa, Nathalie, Larson, Austin, Brown, Kathleen, Wasserstein, Melissa P., Skotko, Brian G., Begtrup, Amber, Person, Richard, Karayiorgou, Maria, Roos, J. Louw, Van Gassen, Koen L., Koopmans, Marije, Bijlsma, Emilia K., Santen, Gijs W.E., Barge-Schaapveld, Daniela Q.C.M., Ruivenkamp, Claudia A.L., Hoffer, Mariette J.V., Lalani, Seema R., Streff, Haley, Craigen, William J., Graham, Brett H., van den Elzen, Annette P.M., Kamphuis, Daan J., Õunap, Katrin, Reinson, Karit, Pajusalu, Sander, Wojcik, Monica H., Viberti, Clara, Di Gaetano, Cornelia, Bertini, Enrico, Petrucci, Simona, De Luca, Alessandro, Rota, Rossella, Ferretti, Elisabetta, Matullo, Giuseppe, Dallapiccola, Bruno, Sgura, Antonella, Walkiewicz, Magdalena, Kooy, R. Frank, and Tartaglia, Marco

Published
2019
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19. Detecting missed diagnoses of spinal muscular atrophy in genome, exome, and panel sequencing datasets

Author

Weisburd, Ben, primary, Sharma, Rakshya, additional, Pata, Villem, additional, Reimand, Tiia, additional, Ganesh, Vijay S., additional, Austin-Tse, Christina, additional, Osei-Owusu, Ikeoluwa, additional, O'Heir, Emily, additional, O'Leary, Melanie, additional, Pais, Lynn, additional, Stafki, Seth A., additional, Daugherty, Audrey L., additional, Bonnemann, Carsten G., additional, Donkervoort, Sandra, additional, Haliloglu, Goknur, additional, Kang, Peter B., additional, Ravenscroft, Gianina, additional, Laing, Nigel, additional, Scott, Hamish S., additional, Topf, Ana, additional, Straub, Volker, additional, Pajusalu, Sander, additional, Ounap, Katrin, additional, Tiao, Grace, additional, Rehm, Heidi L., additional, and O'Donnell-Luria, Anne, additional

Published
2024
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21. Exome sequencing in paediatric patients with movement disorders

Author

Kwong, Anna Ka-Yee, Tsang, Mandy Ho-Yin, Fung, Jasmine Lee-Fong, Mak, Christopher Chun-Yu, Chan, Kate Lok-San, Rodenburg, Richard J. T., Lek, Monkol, Huang, Shushu, Pajusalu, Sander, Yau, Man-Mut, Tsoi, Cheung, Fung, Sharon, Liu, Kam-Tim, Ma, Che-Kwan, Wong, Sheila, Yau, Eric Kin-Cheong, Tai, Shuk-Mui, Fung, Eva Lai-Wah, Wu, Nick Shun-Ping, Tsung, Li-Yan, Smeitink, Jan, Chung, Brian Hon-Yin, and Fung, Cheuk-Wing

Published
2021
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22. Artificial intelligence enables comprehensive genome interpretation and nomination of candidate diagnoses for rare genetic diseases

Author

De La Vega, Francisco M., Chowdhury, Shimul, Moore, Barry, Frise, Erwin, McCarthy, Jeanette, Hernandez, Edgar Javier, Wong, Terence, James, Kiely, Guidugli, Lucia, Agrawal, Pankaj B., Genetti, Casie A., Brownstein, Catherine A., Beggs, Alan H., Löscher, Britt-Sabina, Franke, Andre, Boone, Braden, Levy, Shawn E., Õunap, Katrin, Pajusalu, Sander, Huentelman, Matt, Ramsey, Keri, Naymik, Marcus, Narayanan, Vinodh, Veeraraghavan, Narayanan, Billings, Paul, Reese, Martin G., Yandell, Mark, and Kingsmore, Stephen F.

Published
2021
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23. POLRMT mutations impair mitochondrial transcription causing neurological disease

Author

Oláhová, Monika, Peter, Bradley, Szilagyi, Zsolt, Diaz-Maldonado, Hector, Singh, Meenakshi, Sommerville, Ewen W., Blakely, Emma L., Collier, Jack J., Hoberg, Emily, Stránecký, Viktor, Hartmannová, Hana, Bleyer, Anthony J., McBride, Kim L., Bowden, Sasigarn A., Korandová, Zuzana, Pecinová, Alena, Ropers, Hans-Hilger, Kahrizi, Kimia, Najmabadi, Hossein, Tarnopolsky, Mark A., Brady, Lauren I., Weaver, K. Nicole, Prada, Carlos E., Õunap, Katrin, Wojcik, Monica H., Pajusalu, Sander, Syeda, Safoora B., Pais, Lynn, Estrella, Elicia A., Bruels, Christine C., Kunkel, Louis M., Kang, Peter B., Bonnen, Penelope E., Mráček, Tomáš, Kmoch, Stanislav, Gorman, Gráinne S., Falkenberg, Maria, Gustafsson, Claes M., and Taylor, Robert W.

Published
2021
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24. The phenotypic spectrum of PTCD3 deficiency.

Author

Lace, Baiba, Faqeih, Eissa, Kaya, Namik, Krumina, Zita, Mayr, Johannes A., Micule, Ieva, Wright, Nathan Thompson, Achleitner, Melanie T., AlQudairy, Hanan, Pajusalu, Sander, Stavusis, Janis, Zayakin, Pawel, and Inashkina, Inna

Published
2024
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29. Human skeletal myopathy myosin mutations disrupt myosin head sequestration

Author

Carrington, Glenn, primary, Hau, Abbi, additional, Kosta, Sarah, additional, Dugdale, Hannah F., additional, Muntoni, Francesco, additional, D’Amico, Adele, additional, Van den Bergh, Peter, additional, Romero, Norma B., additional, Malfatti, Edoardo, additional, Vilchez, Juan Jesus, additional, Oldfors, Anders, additional, Pajusalu, Sander, additional, Õunap, Katrin, additional, Giralt-Pujol, Marta, additional, Zanoteli, Edmar, additional, Campbell, Kenneth S., additional, Iwamoto, Hiroyuki, additional, Peckham, Michelle, additional, and Ochala, Julien, additional

Published
2023
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30. Biallelic loss-of-function variants in WBP4, encoding a spliceosome protein, result in a variable neurodevelopmental syndrome

Author

Engal, Eden, primary, Oja, Kaisa Teele, additional, Maroofian, Reza, additional, Geminder, Ophir, additional, Le, Thuy-Linh, additional, Marzin, Pauline, additional, Guimier, Anne, additional, Mor, Evyatar, additional, Zvi, Naama, additional, Elefant, Naama, additional, Zaki, Maha S., additional, Gleeson, Joseph G., additional, Muru, Kai, additional, Pajusalu, Sander, additional, Wojcik, Monica H., additional, Pachat, Divya, additional, Elmaksoud, Marwa Abd, additional, Chan Jeong, Won, additional, Lee, Hane, additional, Bauer, Peter, additional, Zifarelli, Giovanni, additional, Houlden, Henry, additional, Daana, Muhannad, additional, Elpeleg, Orly, additional, Amiel, Jeanne, additional, Lyonnet, Stanislas, additional, Gordon, Christopher T., additional, Harel, Tamar, additional, Õunap, Katrin, additional, Salton, Maayan, additional, and Mor-Shaked, Hagar, additional

Published
2023
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31. Exome copy number variant detection, analysis and classification in a large cohort of families with undiagnosed rare genetic disease

Author

Lemire, Gabrielle, primary, Sanchis-Juan, Alba, additional, Russell, Kathryn, additional, Baxter, Samantha, additional, Chao, Katherine R., additional, Singer-Berk, Moriel, additional, Groopman, Emily, additional, Wong, Isaac, additional, England, Eleina, additional, Goodrich, Julia, additional, Pais, Lynn, additional, Austin-Tse, Christina, additional, DiTroia, Stephanie, additional, O’Heir, Emily, additional, Ganesh, Vijay S., additional, Wojcik, Monica H., additional, Evangelista, Emily, additional, Snow, Hana, additional, Osei-Owusu, Ikeoluwa, additional, Fu, Jack, additional, Singh, Mugdha, additional, Mostovoy, Yulia, additional, Huang, Steve, additional, Garimella, Kiran, additional, Kirkham, Samantha L., additional, Neil, Jennifer E., additional, Shao, Diane D., additional, Walsh, Christopher A., additional, Argili, Emanuela, additional, Le, Carolyn, additional, Sherr, Elliott H., additional, Gleeson, Joseph, additional, Shril, Shirlee, additional, Schneider, Ronen, additional, Hildebrandt, Friedhelm, additional, Sankaran, Vijay G., additional, Madden, Jill A., additional, Genetti, Casie A., additional, Beggs, Alan H., additional, Agrawal, Pankaj B., additional, Bujakowska, Kinga M., additional, Place, Emily, additional, Pierce, Eric A., additional, Donkervoort, Sandra, additional, Bönnemann, Carsten G., additional, Gallacher, Lyndon, additional, Stark, Zornitza, additional, Tan, Tiong, additional, White, Susan M., additional, Töpf, Ana, additional, Straub, Volker, additional, Fleming, Mark D., additional, Pollak, Martin R., additional, Õunap, Katrin, additional, Pajusalu, Sander, additional, Donald, Kirsten A., additional, Bruwer, Zandre, additional, Ravenscroft, Gianina, additional, Laing, Nigel G., additional, MacArthur, Daniel G., additional, Rehm, Heidi L., additional, Talkowski, Michael E., additional, Brand, Harrison, additional, and O’Donnell-Luria, Anne, additional

Published
2023
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33. De novo mutations in MSL3 cause an X-linked syndrome marked by impaired histone H4 lysine 16 acetylation

Author

Basilicata, M. Felicia, Bruel, Ange-Line, Semplicio, Giuseppe, Valsecchi, Claudia Isabelle Keller, Aktaş, Tuğçe, Duffourd, Yannis, Rumpf, Tobias, Morton, Jenny, Bache, Iben, Szymanski, Witold G., Gilissen, Christian, Vanakker, Olivier, Õunap, Katrin, Mittler, Gerhard, van der Burgt, Ineke, El Chehadeh, Salima, Cho, Megan T., Pfundt, Rolph, Tan, Tiong Yang, Kirchhoff, Maria, Menten, Björn, Vergult, Sarah, Lindstrom, Kristin, Reis, André, Johnson, Diana S., Fryer, Alan, McKay, Victoria, DDD Study, Fisher, Richard B., Thauvin-Robinet, Christel, Francis, David, Roscioli, Tony, Pajusalu, Sander, Radtke, Kelly, Ganesh, Jaya, Brunner, Han G., Wilson, Meredith, Faivre, Laurence, Kalscheuer, Vera M., Thevenon, Julien, and Akhtar, Asifa

Published
2018
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34. Death after High-Dose rAAV9 Gene Therapy in a Patient with Duchenne’s Muscular Dystrophy

Author

Lek, Angela, primary, Wong, Brenda, additional, Keeler, Allison, additional, Blackwood, Meghan, additional, Ma, Kaiyue, additional, Huang, Shushu, additional, Sylvia, Katelyn, additional, Batista, A. Rita, additional, Artinian, Rebecca, additional, Kokoski, Danielle, additional, Parajuli, Shestruma, additional, Putra, Juan, additional, Carreon, C. Katte, additional, Lidov, Hart, additional, Woodman, Keryn, additional, Pajusalu, Sander, additional, Spinazzola, Janelle M., additional, Gallagher, Thomas, additional, LaRovere, Joan, additional, Balderson, Diane, additional, Black, Lauren, additional, Sutton, Keith, additional, Horgan, Richard, additional, Lek, Monkol, additional, and Flotte, Terence, additional

Published
2023
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35. Unique Capabilities of Genome Sequencing for Rare Disease Diagnosis

Author

Wojcik, Monica H, primary, Lemire, Gabrielle, additional, Zaki, Maha S, additional, Wissmann, Mariel, additional, Win, Wathone, additional, White, Sue, additional, Weisburd, Ben, additional, Waddell, Leigh B, additional, Verboon, Jeffrey M, additional, VanNoy, Grace E, additional, Topf, Ana, additional, Tan, Tiong Yang, additional, Straub, Volker, additional, Stenton, Sarah L, additional, Snow, Hana, additional, Singer-Berk, Moriel, additional, Silver, Josh, additional, Shril, Shirlee, additional, Seaby, Eleanor G, additional, Schneider, Ronen, additional, Sankaran, Vijay G, additional, Sanchis-Juan, Alba, additional, Russell, Kathryn A, additional, Reinson, Karit, additional, Ravenscroft, Gina, additional, Pierce, Eric A, additional, Place, Emily M, additional, Pajusalu, Sander, additional, Pais, Lynn, additional, Ounap, Katrin, additional, Osei-Owusu, Ikeoluwa, additional, Okur, Volkan, additional, Oja, Kaisa Teele, additional, OLeary, Melanie, additional, OHeir, Emily, additional, Morel, Chantal, additional, Marchant, Rhett G, additional, Mangilog, Brian E, additional, Madden, Jill A, additional, MacArthur, Daniel, additional, Lovgren, Alysia, additional, Lerner-Ellis, Jordan P, additional, Lin, Jasmine, additional, Laing, Nigel, additional, Hildebrandt, Friedhelm, additional, Groopman, Emily, additional, Goodrich, Julia, additional, Gleeson, Joseph G, additional, Ghaoui, Roula, additional, Genetti, Casie A, additional, Gazda, Hanna, additional, Ganesh, Vijay S, additional, Ganapathi, Mythily, additional, Gallacher, Lyndon, additional, Fu, Jack, additional, Evangelista, Emily, additional, England, Eleina, additional, Donkervoort, Sandra, additional, DiTroia, Stephanie, additional, Cooper, Sandra T, additional, Chung, Wendy K, additional, Christodoulou, John, additional, Chao, Katherine R, additional, Cato, Liam D, additional, Bujakowska, Kinga M, additional, Bryen, Samantha J, additional, Brand, Harrison, additional, Bonnemann, Carsten, additional, Beggs, Alan H, additional, Baxter, Samantha M, additional, Agrawal, Pankaj B, additional, Talkowski, Michael, additional, Austin-Tse, Christina, additional, Rehm, Heidi L, additional, and ODonnell-Luria, Anne, additional

Published
2023
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36. Biallelic variants in TSPOAP1, encoding the active-zone protein RIMBP1, cause autosomal recessive dystonia

Author

Mencacci, Niccolo E., Brockmann, Marisa M., Dai, Jinye, Pajusalu, Sander, Atasu, Burcu, Campos, Joaquin, Pino, Gabriela, Gonzalez-Latapi, Paulina, Patzke, Christopher, Schwake, Michael, Tucci, Arianna, Pittman, Alan, Simon-Sanchez, Javier, Carvill, Gemma L., Wiethoff, Bettina Balin Sarah, Warner, Thomas T., Papandreou, Apostolos, Soo, Audrey, Rein, Reet, Kadastik-Eerme, Liis, Puusepp, Sanna, Reinson, Karit, Tomberg, Tiiu, Hanagasi, Hasmet, Gasser, Thomas, Bhatia, Kailash P., Kurian, Manju A., Lohmann, Ebba, Ounap, Katrin, Rosenmund, Christian, Sudhof, Thomas C., Wood, Nicholas W., Krainc, Dimitri, and Acuna, Claudio

Subjects
Care and treatment, Development and progression, Genetic aspects, Health aspects, Synaptic transmission -- Genetic aspects -- Health aspects, Dystonia -- Genetic aspects -- Development and progression -- Care and treatment, Genetic variation -- Health aspects, Binding proteins -- Health aspects, Neural transmission -- Genetic aspects -- Health aspects
Abstract

Introduction Dystonia is a disabling hyperkinetic movement disorder characterized by an excess of sustained, often repetitive, involuntary twisting movements, and abnormal postures (1). Dystonia, after Parkinson's disease and essential tremor, [...], Dystonia is a debilitating hyperkinetic movement disorder, which can be transmitted as a monogenic trait. Here, we describe homozygous frameshift, nonsense, and missense variants in TSPOAP1, which encodes the active-zone RIM-binding protein 1 (RIMBP1), as a genetic cause of autosomal recessive dystonia in 7 subjects from 3 unrelated families. Subjects carrying loss-of-function variants presented with juvenile-onset progressive generalized dystonia, associated with intellectual disability and cerebellar atrophy. Conversely, subjects carrying a pathogenic missense variant (p.Gly1808Ser) presented with isolated adult-onset focal dystonia. In mice, complete loss of RIMBP1, known to reduce neurotransmission, led to motor abnormalities reminiscent of dystonia, decreased Purkinje cell dendritic arborization, and reduced numbers of cerebellar synapses. In vitro analysis of the p.Gly1808Ser variant showed larger spike-evoked calcium transients and enhanced neurotransmission, suggesting that RIMBP1-linked dystonia can be caused by either reduced or enhanced rates of spike-evoked release in relevant neural networks. Our findings establish a direct link between dysfunction of the presynaptic active zone and dystonia and highlight the critical role played by well-balanced neurotransmission in motor control and disease pathogenesis.

Published
2021
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37. Human skeletal myopathy myosin mutations disrupt myosin head sequestration

Author

Carrington, Glenn, Hau, Abbi, Kosta, Sarah, Dugdale, Hannah F., Muntoni, Francesco, D’Amico, Adele, Van den Bergh, Peter, Romero, Norma B., Malfatti, Edoardo, Vilchez, Juan Jesus, Oldfors, Anders, Pajusalu, Sander, Õunap, Katrin, Giralt-Pujol, Marta, Zanoteli, Edmar, Campbell, Kenneth S., Iwamoto, Hiroyuki, Peckham, Michelle, Ochala, Julien, Carrington, Glenn, Hau, Abbi, Kosta, Sarah, Dugdale, Hannah F., Muntoni, Francesco, D’Amico, Adele, Van den Bergh, Peter, Romero, Norma B., Malfatti, Edoardo, Vilchez, Juan Jesus, Oldfors, Anders, Pajusalu, Sander, Õunap, Katrin, Giralt-Pujol, Marta, Zanoteli, Edmar, Campbell, Kenneth S., Iwamoto, Hiroyuki, Peckham, Michelle, and Ochala, Julien

Abstract

Myosin heavy chains encoded by MYH7 and MYH2 are abundant in human skeletal muscle and important for muscle contraction. However, it is unclear how mutations in these genes disrupt myosin structure and function leading to skeletal muscle myopathies termed myosinopathies. Here, we used multiple approaches to analyze the effects of common MYH7 and MYH2 mutations in the light meromyosin (LMM) region of myosin. Analyses of expressed and purified MYH7 and MYH2 LMM mutant proteins combined with in silico modeling showed that myosin coiled coil structure and packing of filaments in vitro are commonly disrupted. Using muscle biopsies from patients and fluorescent ATP analog chase protocols to estimate the proportion of myosin heads that were super-relaxed, together with x-ray diffraction measurements to estimate myosin head order, we found that basal myosin ATP consumption was increased and the myosin super-relaxed state was decreased in vivo. In addition, myofiber mechanics experiments to investigate contractile function showed that myofiber contractility was not affected. These findings indicate that the structural remodeling associated with LMM mutations induces a pathogenic state in which formation of shutdown heads is impaired, thus increasing myosin head ATP demand in the filaments, rather than affecting contractility. These key findings will help design future therapies for myosinopathies.

Published
2023

38. Biallelic loss of function variants inWBP4, encoding a spliceosome protein, result in a variable neurodevelopmental delay syndrome

Author

Engal, Eden, primary, Oja, Kaisa Teele, additional, Maroofian, Reza, additional, Geminder, Ophir, additional, Le, Thuy-Linh, additional, Mor, Evyatar, additional, Tzvi, Naama, additional, Elefant, Naama, additional, Zaki, Maha S., additional, Gleeson, Joseph G., additional, Muru, Kai, additional, Pajusalu, Sander, additional, Wojcik, Monica H., additional, Pachat, Divya, additional, Elmaksoud, Marwa Abd, additional, Jeong, Won Chan, additional, Lee, Hane, additional, Bauer, Peter, additional, Zifarelli, Giovanni, additional, Houlden, Henry, additional, Elpeleg, Orly, additional, Gordon, Chris, additional, Harel, Tamar, additional, Õunap, Katrin, additional, Salton, Maayan, additional, and Mor-Shaked, Hagar, additional

Published
2023
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39. Unexpected Death of a Duchenne Muscular Dystrophy Patient in an N-of-1 Trial of rAAV9-delivered CRISPR-transactivator

Author

Lek, Angela, primary, Wong, Brenda, additional, Keeler, Allison, additional, Blackwood, Meghan, additional, Ma, Kaiyue, additional, Huang, Shushu, additional, Sylvia, Katelyn, additional, Batista, Ana Rita, additional, Artinian, Rebecca, additional, Kokoski, Danielle, additional, Parajuli, Shestruma, additional, Putra, Juan, additional, Carreon, Chrystalle Katte, additional, Lidov, Hart, additional, Woodman, Keryn, additional, Pajusalu, Sander, additional, Spinazzola, Janelle, additional, Gallagher, Thomas, additional, LaRovere, Joan, additional, Baulderson, Diane, additional, Black, Lauren, additional, Sutton, Keith, additional, Horgan, Richard, additional, Lek, Monkol, additional, and Flotte, Terence, additional

Published
2023
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40. Human light meromyosin mutations linked to skeletal myopathies disrupt the coiled coil structure and myosin head sequestration

Author

Carrington, Glenn, primary, Hau, Abbi, additional, Kosta, Sarah, additional, Dugdale, Hannah, additional, Muntoni, Francesco, additional, D'Amico, Adele, additional, Van den Bergh, Peter, additional, Romero, Norma, additional, Malfatti, Edoardo, additional, Vilchez, Juan Jesus, additional, Oldfors, Anders, additional, Pajusalu, Sander, additional, Ounap, Katrin, additional, Giralt-Pujol, Marta, additional, Zanoteli, Edmar, additional, Campbell, Kenneth, additional, Iwamoto, Hiroyuki, additional, Peckham, Michelle, additional, and Ochala, Julien, additional

Published
2023
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43. Bi-allelic loss-of-function variants in WBP4, encoding a spliceosome protein, result in a variable neurodevelopmental syndrome

Author

Engal, Eden, Oja, Kaisa Teele, Maroofian, Reza, Geminder, Ophir, Le, Thuy-Linh, Marzin, Pauline, Guimier, Anne, Mor, Evyatar, Zvi, Naama, Elefant, Naama, Zaki, Maha S., Gleeson, Joseph G., Muru, Kai, Pajusalu, Sander, Wojcik, Monica H., Pachat, Divya, Elmaksoud, Marwa Abd, Chan Jeong, Won, Lee, Hane, Bauer, Peter, Zifarelli, Giovanni, Houlden, Henry, Daana, Muhannad, Elpeleg, Orly, Amiel, Jeanne, Lyonnet, Stanislas, Gordon, Christopher T., Harel, Tamar, Õunap, Katrin, Salton, Maayan, and Mor-Shaked, Hagar

Published
2023
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44. Compound heterozygous SPATA5 variants in four families and functional studies of SPATA5 deficiency

Author

Puusepp, Sanna, Kovacs-Nagy, Reka, Alhaddad, Bader, Braunisch, Matthias, Hoffmann, Georg F., Kotzaeridou, Urania, Lichvarova, Lucia, Liiv, Mailis, Makowski, Christine, Mandel, Merle, Meitinger, Thomas, Pajusalu, Sander, Rodenburg, Richard J., Safiulina, Dzhamilja, Strom, Tim M., Talvik, Inga, Vaarmann, Annika, Wilson, Callum, Kaasik, Allen, Haack, Tobias B., and Õunap, Katrin

Published
2018
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45. sj-docx-3-jcn-10.1177_08830738231186233 - Supplemental material for High Prevalence of Collagenopathies in Preterm- and Term-Born Children With Periventricular Venous Hemorrhagic Infarction

Author

Ilves, Norman, Pajusalu, Sander, Kahre, Tiina, Laugesaar, Rael, Šamarina, Ustina, Loorits, Dagmar, Kool, Pille, and Ilves, Pilvi

Subjects
Neurology and Neuromuscular Diseases, FOS: Clinical medicine, Paediatrics, Neuroscience
Abstract

Supplemental material, sj-docx-3-jcn-10.1177_08830738231186233 for High Prevalence of Collagenopathies in Preterm- and Term-Born Children With Periventricular Venous Hemorrhagic Infarction by Norman Ilves, Sander Pajusalu, Tiina Kahre, Rael Laugesaar, Ustina Šamarina, Dagmar Loorits, Pille Kool and Pilvi Ilves in Journal of Child Neurology

Published
2023
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46. Untargeted metabolomics profiling in pediatric patients and adult populations indicates a connection between lipid imbalance and epilepsy

Author

Oja, Kaisa Teele, primary, Ilisson, Mihkel, additional, Reinson, Karit, additional, Muru, Kai, additional, Reimand, Tiia, additional, Peterson, Hedi, additional, Fishman, Dmytro, additional, Esko, Tõnu, additional, Haller, Toomas, additional, Kronberg, Jaanika, additional, Wojcik, Monica H., additional, Kennedy, Adam, additional, Michelotti, Gregory, additional, O’Donnell-Luria, Anne, additional, Õiglane-Šlik, Eve, additional, Pajusalu, Sander, additional, and Õunap, Katrin, additional

Published
2023
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47. P452: Specifying the ACMG/AMP variant sequence interpretation guidelines for congenital myopathies*

Author

DiStefano, Marina, primary, Webb, Ryan, additional, McCurry, Hannah, additional, McNulty Gray, Shannon, additional, Tomar, Swati, additional, Kopparapu, Prasad, additional, Broeren, Eleanor, additional, Tshering, Kezang, additional, Beggs, Alan, additional, Bertini, Enrico Silvio, additional, D'Amico, Adele, additional, Donkervoort, Sandra, additional, Dowling, James, additional, Fattori, Fabiana, additional, Ferreiro, Ana, additional, Genetti, Casie, additional, Gonorazky, Hernan, additional, Gorokhova, Svetlana, additional, Lindy, Amanda, additional, Medne, Livija, additional, Pajusalu, Sander, additional, Pelin, Katarina, additional, Rendu, John, additional, Vatta, Matteo, additional, Winder, Tom, additional, Yang, Hui, additional, Yoon, Grace, additional, Ceyhan-Birsoy, Ozge, additional, and Bönnemann, Carsten, additional

Published
2023
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48. The Prevalence and Molecular Landscape of Lynch Syndrome in the Affected and General Population.

Author

Roht, Laura, Laidre, Piret, Tooming, Mikk, Tõnisson, Neeme, Nõukas, Margit, Nurm, Miriam, Roomere, Hanno, Rekker, Kadri, Toome, Kadri, Fjodorova, Olga, Murumets, Ülle, Šamarina, Ustina, Pajusalu, Sander, Aaspõllu, Anu, Salumäe, Liis, Muhu, Kristina, Soplepmann, Jaan, Õunap, Katrin, and Kahre, Tiina

Subjects
CONFIDENCE intervals, SEQUENCE analysis, IMMUNOHISTOCHEMISTRY, HEREDITARY nonpolyposis colorectal cancer, GENETIC testing, MOLECULAR biology, GENETIC markers, DISEASE susceptibility, RESEARCH funding, DESCRIPTIVE statistics, DATA analysis software, ODDS ratio, LONGITUDINAL method
Abstract

Simple Summary: Lynch syndrome accounts for 2–3% of all CRC cases. This retroactive and prospective study aimed to estimate the prevalence of Lynch syndrome and describe disease-causing variants in mismatch repair genes in a diagnostic setting and in the Estonian general population. For that, ten years (2012–2022) of data was gathered. In addition, a pilot study for estimating the improvement of Lynch syndrome diagnostics by raising the age limit of mismatch repair gene immunohistochemistry was conducted. We estimated the birth prevalence of LS in Estonia at 1:8638 (95% CI: 1:9859–7588) or 11.58 (95% CI: 10.14–13.18) for 100,000 LBs between 1930 and 2003. The prevalence of Lynch syndrome has increased approximately six-fold in ten years. Due to the improvement of awareness in families and patients sharing information with their family members, the latter receives the diagnosis eight years earlier when most individuals are still healthy, illustrating the benefit of genetic testing and therefore an opportunity for prevention. Furthermore, the pilot study proved to be beneficial. Background: Lynch syndrome (LS) is the most frequent genetically pre-disposed colorectal cancer (CRC) syndrome, accounting for 2–3% of all CRC cases. In Estonia, ~1000 new cases are diagnosed each year. This retroactive and prospective study aimed to estimate the prevalence of LS and describe disease-causing variants in mismatch repair (MMR) genes in a diagnostic setting and in the Estonian general population. Methods: LS data for the diagnostic cohort were gathered from 2012 to 2022 and data for the general population were acquired from the Estonian Biobank (EstBB). Furthermore, we conducted a pilot study to estimate the improvement of LS diagnostic yield by raising the age limit to >50 years for immunohistochemistry analysis of MMR genes. Results: We estimated LS live birth prevalence between 1930 and 2003 in Estonia at 1:8638 (95% CI: 1: 9859–7588). During the study period, we gathered 181 LS individuals. We saw almost a six-fold increase in case prevalence, probably deriving from better health awareness, improved diagnostic possibilities and the implementation of MMR IHC testing in a broader age group. Conclusion: The most common genes affected in the diagnostic and EstBB cohorts were MLH1 and PMS2 genes, respectively. The LS diagnosis mean age was 44.8 years for index cases and 36.8 years (p = 0.003) for family members. In the MMR IHC pilot study, 29% had LS. [ABSTRACT FROM AUTHOR]

Published
2023
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