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7 results on '"Sylvia Dobrzeniecka"'

1. High Rate of Recurrent De Novo Mutations in Developmental and Epileptic Encephalopathies

Author

Patrick Cossette, Zoha Kibar, Maxime Cadieux-Dion, Helen Brittain, Andrew E. Fry, Emily Fassi, Edward Blair, Simone Martinelli, Paul J. Benke, Guy D'Anjou, Alexandre D. Laporte, Berge A. Minassian, Sylvia Stockler, Tyson L Ware, David R. FitzPatrick, Weimin Bi, Amy L Schneider, Jill A. Rosenfeld, Shekeeb S. Mohammad, Jacques L. Michaud, Carlos A. Bacino, Joss Shelagh, Samuel F. Berkovic, Stéphane Auvin, Yunru Shao, Sylvia Dobrzeniecka, Kelly Mo, Cory Tam, Nicole Corsten-Janssen, Wendy K. Chung, Renee-Myriam Boucher, Alain Verloes, Fadi F. Hamdan, Bronwyn Kerr, Frédéric Tran Mau-Them, Martina Bebin, Philippe M. Campeau, Dara V.F. Albert, Guy A. Rouleau, Quinn Stein, Anne Lortie, Susan M. Hiatt, Lubov Blumkin, Boris Keren, Dan Spiegelman, Saadet Mercimek-Mahmutoglu, Ronald G. Lafrenière, Marie-Christine Nougues, Rhys H. Thomas, Erica H. Gerkes, Elsa Rossignol, Bruno Dallapiccola, Klaas J. Wierenga, Natalie Canham, Monica H. Wojcik, Caroline Meloche, Moira Blyth, Cyril Mignot, Heather C Mefford, Ledia Brunga, D. L. Jones, François Dubeau, Kyle Retterer, James J. O'Byrne, Christine Massicotte, Vincenzo Leuzzi, Caroline Nava, Ingrid E. Scheffer, Erik-Jan Kamsteeg, Cyrus Boelman, Megan T. Cho, Gabriela Purcarin, Brigid M. Regan, Jean Monlong, Simon Girard, Philippe Major, Marguerite Miguet, Katrin Õunap, Yu Chi Liu, Guillaume Bourque, Myriam Srour, Ousmane Diallo, Emilie Riou, Lionel Carmant, Seema R. Lalani, Christina Nassif, Robert Roger Lebel, Anna Lehman, Georgie Hollingsworth, Stéphanie Jacques, Sunita Venkateswaran, Marco Tartaglia, Candace T. Myers, Ange-Line Bruel, Danielle M. Andrade, Imad Jarjour, Peyman Bizargity, Sara J. Dorison, Jane A. Hurst, Richard E. Frye, Lynette G. Sadleir, Alan Donaldson, Fernando Scaglia, Philippe Lemay, Paola Diadori, Laura Davis-Keppen, Division of Genetic Medicine [Seattle], University of Washington [Seattle], Centre hospitalier universtaire de Montréal, Université de Montréal, Baylor College of Medicine ( BCM ), Baylor College of Medicine, Laboratoire de Diagnostic Génétique, CHU Strasbourg-Hopital Civil, Clinical Genetics Department, St Michael's Hospital, Department of Clinical Genetics, Oxford Regional Genetics Service, The Churchill hospital, Regional Genetic Service, St Mary's Hospital, Manchester, SUNY Upstate Medical University, Centre de génétique - Centre de référence des maladies rares, anomalies du développement et syndromes malformatifs (CHU de Dijon), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand ( CHU Dijon ), Equipe GAD (LNC - U1231), Lipides - Nutrition - Cancer [Dijon - U1231] ( LNC ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Université de Bourgogne ( UB ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Institut National de la Santé et de la Recherche Médicale ( INSERM ), Hôpital Robert Debré, Universitätsklinikum Leipzig, Institute of Plant and Microbial Biology, Academia Sinica, Istituto di Genetica Medica, Medical Genetics and Pediatric Cardiology, IRCCS Ospedale Pediatrico Bambino Gesù [Roma], Ematologia, Oncologia e Medicina Molecolare, Istituto Superiore di Sanita', Service de Génétique Cytogénétique et Embryologie [CHU Pitié-Salpêtrière], Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], Service de génétique, cytogénétique, embryologie [Pitié-Salpétrière], Université Pierre et Marie Curie - Paris 6 ( UPMC ) -Assistance publique - Hôpitaux de Paris (AP-HP)-CHU Pitié-Salpêtrière [APHP], 'Personal Protection Against Vectors' working group ( PPAV ), PPAV working group, Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute ( ICM ), Centre National de la Recherche Scientifique ( CNRS ) -CHU Pitié-Salpêtrière [APHP]-Institut National de la Santé et de la Recherche Médicale ( INSERM ) -Université Pierre et Marie Curie - Paris 6 ( UPMC ), Département de Mathématiques, Université de Sherbrooke, Université de Sherbrooke [Sherbrooke], McGill University and Genome Quebec Innovation Centre, Center of Excellence in Neuromics, University of Montreal, The Hospital for sick children [Toronto] ( SickKids ), CHU Sainte Justine [Montréal], Genome Canada Genome Quebec Jeanne and Jean-Louis Levesque Foundation Michael Bahen Chair in Epilepsy Research Ontario Brain Institute McLaughlin Foundation University of Toronto National Institute of Neurological Disorders and Stroke RO1 NS069605 University of Toronto McLaughlin Accelerator Grant in Genomic Medicine MC-2013-08, Baylor College of Medicine (BCM), Baylor University, State University of New York (SUNY), Centre Hospitalier Universitaire de Dijon - Hôpital François Mitterrand (CHU Dijon), 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, 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, Istituto Superiore di Sanità (ISS), CHU Pitié-Salpêtrière [AP-HP], Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), 'Personal Protection Against Vectors' working group (PPAV), Institut du Cerveau et de la Moëlle Epinière = Brain and Spine Institute (ICM), Université Pierre et Marie Curie - Paris 6 (UPMC)-Institut National de la Santé et de la Recherche Médicale (INSERM)-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)-Centre National de la Recherche Scientifique (CNRS), Département de mathématiques [Sherbrooke] (UdeS), Faculté des sciences [Sherbrooke] (UdeS), Université de Sherbrooke (UdeS)-Université de Sherbrooke (UdeS), The Hospital for sick children [Toronto] (SickKids), Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU), and Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Assistance publique - Hôpitaux de Paris (AP-HP) (AP-HP)-Sorbonne Université (SU)-Université Pierre et Marie Curie - Paris 6 (UPMC)

Subjects
Male, 0301 basic medicine, Candidate gene, medicine.medical_specialty, medical genetics, glycosylation, Nonsense mutation, Genome-wide association study, Gene mutation, Biology, Sensory disorders Donders Center for Medical Neuroscience [Radboudumc 12], Article, severe intellectual disability, 03 medical and health sciences, Epilepsy, 0302 clinical medicine, children, Recurrence, Seizures, Genetic linkage, Intellectual Disability, [ SDV.MHEP ] Life Sciences [q-bio]/Human health and pathology, Journal Article, Genetics, medicine, Humans, Child, disorders, Genetics (clinical), Genetic association, Brain Diseases, disease, cis-prenyltransferase, Genome, Human, structural basis, medicine.disease, diphosphate synthase, 030104 developmental biology, Child, Preschool, Mutation, Medical genetics, Female, nogo-b receptor, 030217 neurology & neurosurgery, [SDV.MHEP]Life Sciences [q-bio]/Human health and pathology, Genome-Wide Association Study, Meta-Analysis
Abstract

Item does not contain fulltext Developmental and epileptic encephalopathy (DEE) is a group of conditions characterized by the co-occurrence of epilepsy and intellectual disability (ID), typically with developmental plateauing or regression associated with frequent epileptiform activity. The cause of DEE remains unknown in the majority of cases. We performed whole-genome sequencing (WGS) in 197 individuals with unexplained DEE and pharmaco-resistant seizures and in their unaffected parents. We focused our attention on de novo mutations (DNMs) and identified candidate genes containing such variants. We sought to identify additional subjects with DNMs in these genes by performing targeted sequencing in another series of individuals with DEE and by mining various sequencing datasets. We also performed meta-analyses to document enrichment of DNMs in candidate genes by leveraging our WGS dataset with those of several DEE and ID series. By combining these strategies, we were able to provide a causal link between DEE and the following genes: NTRK2, GABRB2, CLTC, DHDDS, NUS1, RAB11A, GABBR2, and SNAP25. Overall, we established a molecular diagnosis in 63/197 (32%) individuals in our WGS series. The main cause of DEE in these individuals was de novo point mutations (53/63 solved cases), followed by inherited mutations (6/63 solved cases) and de novo CNVs (4/63 solved cases). De novo missense variants explained a larger proportion of individuals in our series than in other series that were primarily ascertained because of ID. Moreover, these DNMs were more frequently recurrent than those identified in ID series. These observations indicate that the genetic landscape of DEE might be different from that of ID without epilepsy.

Published
2017
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2. Exome sequencing identifies recessive CDK5RAP2 variants in patients with isolated agenesis of corpus callosum

Author

Patrick A. Dion, Daniel Rochefort, Hugo Théoret, Maryse Lassonde, Sylvia Dobrzeniecka, Loubna Jouan, Alexandre Dionne-Laporte, Pascale Hince, Guy A. Rouleau, Bouchra Ouled Amar Bencheikh, Dan Spiegelman, Anna Szuto, Marine Barbelanne, Hussein Daoud, and William Y. Tsang

Subjects
0301 basic medicine, Adult, Male, Heterozygote, Short Report, Mutation, Missense, Cell Cycle Proteins, Nerve Tissue Proteins, Biology, Corpus callosum, Compound heterozygosity, Bioinformatics, Pathogenesis, 03 medical and health sciences, 0302 clinical medicine, Genetics, medicine, Humans, Exome, Agenesis of the corpus callosum, Gene, Genetics (clinical), Exome sequencing, CDK5RAP2, Siblings, Intracellular Signaling Peptides and Proteins, Middle Aged, medicine.disease, 030104 developmental biology, nervous system, Agenesis, Female, Agenesis of Corpus Callosum, 030217 neurology & neurosurgery
Abstract

Agenesis of the corpus callosum (ACC) is a common brain malformation which can be observed either as an isolated condition or as part of numerous congenital syndromes. Therefore, cognitive and neurological involvements in patients with ACC are variable, from mild linguistic and behavioral impairments to more severe neurological deficits. To date, the underlying genetic causes of isolated ACC remains elusive and causative genes have yet to be identified. We performed exome sequencing on three acallosal siblings from the same non-consanguineous family and identified compound heterozygous variants, p.[Gly94Arg];[Asn1232Ser], in the protein encoded by the CDK5RAP2 gene, also known as MCPH3, a gene previously reported to cause autosomal recessive primary microcephaly. Our findings suggest a novel role for this gene in the pathogenesis of isolated ACC.

Published
2015

3. Deficiency of Asparagine Synthetase Causes Congenital Microcephaly and a Progressive Form of Encephalopathy

Author

Jacques L. Michaud, Jean-Claude Décarie, Danit Oz-Levi, Mark E. Samuels, Haike Reznik-Wolf, Kimberly Pelak, Yuki Hitomi, Yong-hui Jiang, Grant A. Mitchell, Fadi F. Hamdan, Laurence Colleaux, Xiao-Ping He, Abul Hasnat, Esther Leshinsky-Silver, Yi-Fan Lu, Elizabeth K. Ruzzo, Tally Lerman-Sagie, Sylvia Dobrzeniecka, Xiaodi Yao, Andrea L. Pappas, David Chitayat, Rasesh B. Joshi, David Goldstein, Hanqian Mao, Ramona M. Rodriguiz, Brenda Banwell, William C. Wetsel, Mohammad Safiqul Islam, Tsviya Olender, Jose-Mario Capo-Chichi, Debra L. Silver, Rachel Silver, Doron Lancet, Edna Ben-Asher, James O. McNamara, Lysanne Patry, Bruria Ben-Zeev, Ifat Bar-Joseph, Dorit Lev, Susan Blaser, Dipendra K. Aryal, Guy A. Rouleau, Yair Anikster, Elon Pras, Center of Excellence in Neuroscience of Université de Montréal [Canada], CHU Sainte Justine [Montréal]-Centre de Recherche du CHU Sainte-Justine [Montréal, Canada], University of Toronto, Duke University [Durham], CHU Sainte Justine [Montréal], Institute of Medical Genetics, Wolfson Medical Center, Sheba Medical Center, Imagine - Institut des maladies génétiques (IMAGINE - U1163), Centre National de la Recherche Scientifique (CNRS)-Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Pennsylvania [Philadelphia], Discipline of Computer Science, Faculty of Science and Technology, Queensland University of Technology [Brisbane] (QUT), Laboratoire Hubert Curien [Saint Etienne] (LHC), Institut d'Optique Graduate School (IOGS)-Université Jean Monnet [Saint-Étienne] (UJM)-Centre National de la Recherche Scientifique (CNRS), Montreal Neurological Institute and Hospital, McGill University, Université Paris Descartes - Paris 5 (UPD5)-Institut National de la Santé et de la Recherche Médicale (INSERM), Université Jean Monnet [Saint-Étienne] (UJM)-Centre National de la Recherche Scientifique (CNRS)-Institut d'Optique Graduate School (IOGS), and McGill University = Université McGill [Montréal, Canada]

Subjects
Male, medicine.medical_specialty, Microcephaly, Adolescent, Neuroscience(all), Asparagine synthetase, Encephalopathy, Mutation, Missense, Mice, Transgenic, Biology, medicine.disease_cause, Article, Mice, 03 medical and health sciences, 0302 clinical medicine, Atrophy, Intellectual Disability, Internal medicine, medicine, Animals, Humans, Missense mutation, Genetic Predisposition to Disease, Asparagine, Child, 030304 developmental biology, Genetics, Cerebral atrophy, 0303 health sciences, Mutation, General Neuroscience, Infant, Newborn, Brain, Infant, Aspartate-Ammonia Ligase, Syndrome, medicine.disease, Pedigree, Endocrinology, [SDV.GEN.GH]Life Sciences [q-bio]/Genetics/Human genetics, Female, 030217 neurology & neurosurgery
Abstract

International audience; We analyzed four families that presented with a similar condition characterized by congenital micro-cephaly, intellectual disability, progressive cerebral atrophy, and intractable seizures. We show that recessive mutations in the ASNS gene are responsible for this syndrome. Two of the identified missense mutations dramatically reduce ASNS protein abundance, suggesting that the mutations cause loss of function. Hypomorphic Asns mutant mice have structural brain abnormalities, including enlarged ventricles and reduced cortical thickness, and show deficits in learning and memory mimicking aspects of the patient phenotype. ASNS encodes asparagine synthetase, which catalyzes the synthesis of asparagine from glutamine and aspartate. The neurological impairment resulting from ASNS deficiency may be explained by asparagine depletion in the brain or by accumulation of aspartate/gluta-mate leading to enhanced excitability and neuronal damage. Our study thus indicates that asparagine synthesis is essential for the development and function of the brain but not for that of other organs.

Published
2013
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4. Excess of De Novo Deleterious Mutations in Genes Associated with Glutamatergic Systems in Nonsyndromic Intellectual Disability

Author

Jacques L. Michaud, Ronald G. Lafrenière, Jae-Ran Lee, A-Reum Park, Michael Shevell, Hideyuki Tomitori, Yuhki Yoshizawa, Guy A. Rouleau, Michel Vanasse, Sylvia Dobrzeniecka, Jean-Claude Lacaille, Amélie Nadeau, Eunjoon Kim, Richard L. Huganir, Dan Spiegelman, Amélie Piton, Claude Marineau, Fadi F. Hamdan, Hussein Daoud, Guy D'Anjou, Pierre Drapeau, Bruno Maranda, Grant A. Mitchell, Kazuei Igarashi, Ousmane Diallo, Edouard Henrion, Masoud Shekarabi, Yoichi Araki, Christine Massicotte, Myriam Srour, Kyohei Higashi, Da Ting Lin, and Julie Gauthier

Subjects
Male, Kinesins, SYNGAP1, medicine.disease_cause, 0302 clinical medicine, Intellectual disability, Missense mutation, Genetics(clinical), Genetics (clinical), KIF1A, Genetics, 0303 health sciences, Mutation, Syndrome, 3. Good health, Protein Transport, Phenotype, Female, Erratum, Neutral mutation, Protein Binding, Subcellular Fractions, RNA Splicing, Mutation, Missense, Glutamic Acid, Biology, Receptors, N-Methyl-D-Aspartate, Article, Frameshift mutation, 03 medical and health sciences, Glutamatergic, Intellectual Disability, medicine, Animals, Humans, Receptors, AMPA, Gene, 030304 developmental biology, Base Sequence, Neuropeptides, GRIN1, Membrane Proteins, medicine.disease, Human genetics, 030227 psychiatry, Rats, Cytoskeletal Proteins, HEK293 Cells, Amino Acid Substitution, biology.protein, Calcium Channels, 030217 neurology & neurosurgery
Abstract

Little is known about the genetics of nonsyndromic intellectual disability (NSID). We hypothesized that de novo mutations (DNMs) in synaptic genes explain an important fraction of sporadic NSID cases. In order to investigate this possibility, we sequenced 197 genes encoding glutamate receptors and a large subset of their known interacting proteins in 95 sporadic cases of NSID. We found 11 DNMs, including ten potentially deleterious mutations (three nonsense, two splicing, one frameshift, four missense) and one neutral mutation (silent) in eight different genes. Calculation of point-substitution DNM rates per functional and neutral site showed significant excess of functional DNMs compared to neutral ones. De novo truncating and/or splicing mutations in SYNGAP1, STXBP1, and SHANK3 were found in six patients and are likely to be pathogenic. De novo missense mutations were found in KIF1A, GRIN1, CACNG2, and EPB41L1. Functional studies showed that all these missense mutations affect protein function in cell culture systems, suggesting that they may be pathogenic. Sequencing these four genes in 50 additional sporadic cases of NSID identified a second DNM in GRIN1 (c.1679_1681dup/p.Ser560dup). This mutation also affects protein function, consistent with structural predictions. None of these mutations or any other DNMs were identified in these genes in 285 healthy controls. This study highlights the importance of the glutamate receptor complexes in NSID and further supports the role of DNMs in this disorder.

Published
2011
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5. De novo SYNGAP1 mutations in nonsyndromic intellectual disability and autism

Author

Jean-Claude Lacaille, Amélie Nadeau, Ridha Joober, Fadi F. Hamdan, Miriam H. Beauchamp, Amélie Piton, Guy A. Rouleau, Jeff M. Milunsky, Sylvia Dobrzeniecka, Zhenyuan Wang, Julie Gauthier, Laurent Mottron, Lionel Carmant, Jacques L. Michaud, Marie-Odile Krebs, and Hussein Daoud

Subjects
Adult, Male, medicine.medical_specialty, Genotype, SYNGAP1, medicine.disease_cause, 03 medical and health sciences, Exon, Epilepsy, 0302 clinical medicine, Intellectual Disability, Intellectual disability, medicine, Humans, Generalized epilepsy, Autistic Disorder, Psychiatry, Biological Psychiatry, Genetic Association Studies, 030304 developmental biology, Genetics, 0303 health sciences, Mutation, Exons, medicine.disease, 3. Good health, Developmental disorder, Codon, Nonsense, ras GTPase-Activating Proteins, Autism, Female, Psychology, 030217 neurology & neurosurgery
Abstract

Background Little is known about the genetics of nonsyndromic intellectual disability (NSID). Recently, we reported de novo truncating mutations in the SYNGAP1 gene of 3 of 94 NSID cases, suggesting that its disruption represents a common cause of autosomal dominant NSID. Methods To further explore the involvement of SYNGAP1 in NSID, we sequenced its exons and intronic boundaries in 60 additional sporadic cases of NSID, including 30 patients with autism spectrum disorders (ASD) and 9 with epilepsy, and in 380 control individuals. Results We identified de novo out-of-frame deletions in two patients with NSID and mild generalized epilepsy (c.2677delC/p.Q893RfsX184 and c.321_324delGAAG/p. K108VfsX25) and a de novo splicing mutation (c.2294 + 1G>A), which results in the creation of a premature stop codon, in a patient with NSID and autism. No splicing or truncating mutations were found in control subjects. Conclusions We provide evidence that truncating mutations in SYNGAP1 are common in NSID and can be also associated with autism.

Published
2010

6. De Novo Mutations in FOXP1 in Cases with Intellectual Disability, Autism, and Language Impairment

Author

Ridha Joober, Guy A. Rouleau, Pierre Drapeau, Eric Fombonne, Jacques L. Michaud, Sylvia Dobrzeniecka, Laurent Mottron, Miriam H. Beauchamp, Mathieu Langlois, Fadi F. Hamdan, Gila Foomani, Amélie Piton, Jean-Claude Lacaille, Hussein Daoud, Michael S. Phillips, Marie-Odile Krebs, Julie Gauthier, Ronald G. Lafrenière, and Daniel Rochefort

Subjects
Male, Adolescent, Molecular Sequence Data, Nonsense mutation, Mood Lability, 03 medical and health sciences, Exon, 0302 clinical medicine, Intellectual Disability, Report, Intellectual disability, Genetics, medicine, Humans, Genetics(clinical), Amino Acid Sequence, Child, Developmental verbal dyspraxia, Genetics (clinical), 030304 developmental biology, Language Disorders, 0303 health sciences, business.industry, Forkhead Transcription Factors, FOXP2, FOXP1, medicine.disease, Repressor Proteins, Child Development Disorders, Pervasive, Child, Preschool, Mutation, Autism, Female, business, 030217 neurology & neurosurgery
Abstract

Heterozygous mutations in FOXP2, which encodes a forkhead transcription factor, have been shown to cause developmental verbal dyspraxia and language impairment. FOXP2 and its closest homolog, FOXP1, are coexpressed in brain regions that are important for language and cooperatively regulate developmental processes, raising the possibility that FOXP1 may also be involved in developmental conditions that are associated with language impairment. In order to explore this possibility, we searched for mutations in FOXP1 in patients with intellectual disability (ID; mental retardation) and/or autism spectrum disorders (ASD). We first performed array-based genomic hybridization on sporadic nonsyndromic ID (NSID) (n = 30) or ASD (n = 80) cases. We identified a de novo intragenic deletion encompassing exons 4–14 of FOXP1 in a patient with NSID and autistic features. In addition, sequencing of all coding exons of FOXP1 in sporadic NSID (n = 110) or ASD (n = 135) cases, as well as in 570 controls, revealed the presence of a de novo nonsense mutation (c.1573C>T [p.R525X]) in the conserved forkhead DNA-binding domain in a patient with NSID and autism. Luciferase reporter assays showed that the p.R525X alteration disrupts the activity of the protein. Formal assessments revealed that both patients with de novo mutations in FOXP1 also show severe language impairment, mood lability with physical aggressiveness, and specific obsessions and compulsions. In conclusion, both FOXP1 and FOXP2 are associated with language impairment, but decrease of the former has a more global impact on brain development than that of the latter.

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7. Mutations in C5ORF42 Cause Joubert Syndrome in the French Canadian Population

Author

Valérie Désilets, Jacques L. Michaud, Christine Massicotte, Guy A. Rouleau, Bruno Maranda, Simon Papillon-Cavanagh, Sylvia Dobrzeniecka, Jacek Majewski, Rachel Laframboise, Mark E. Samuels, Luis H. Ospina, Lysanne Patry, Myriam Srour, Jose-Mario Capo-Chichi, Jeremy Schwartzentruber, Kym M. Boycott, Fadi F. Hamdan, Michael Shevell, and Damian Labuda

Subjects
Adult, Male, Canada, Heterozygote, Molecular Sequence Data, Population, Biology, Compound heterozygosity, Polymorphism, Single Nucleotide, Retina, Joubert syndrome, 03 medical and health sciences, 0302 clinical medicine, Cerebellar Diseases, Cerebellum, Report, Genetics, medicine, Humans, Missense mutation, Genetics(clinical), Abnormalities, Multiple, Exome, Eye Abnormalities, Child, education, Genetics (clinical), Exome sequencing, 030304 developmental biology, 0303 health sciences, education.field_of_study, Base Sequence, Homozygote, Membrane Proteins, Kidney Diseases, Cystic, medicine.disease, Exon skipping, Hypotonia, Child, Preschool, Mutation, Female, medicine.symptom, 030217 neurology & neurosurgery
Abstract

Joubert syndrome (JBTS) is an autosomal-recessive disorder characterized by a distinctive mid-hindbrain malformation, developmental delay with hypotonia, ocular-motor apraxia, and breathing abnormalities. Although JBTS was first described more than 40 years ago in French Canadian siblings, the causal mutations have not yet been identified in this family nor in most French Canadian individuals subsequently described. We ascertained a cluster of 16 JBTS-affected individuals from 11 families living in the Lower St. Lawrence region. SNP genotyping excluded the presence of a common homozygous mutation that would explain the clustering of these individuals. Exome sequencing performed on 15 subjects showed that nine affected individuals from seven families (including the original JBTS family) carried rare compound-heterozygous mutations in C5ORF42. Two missense variants (c.4006C>T [p.Arg1336Trp] and c.4690G>A [p.Ala1564Thr]) and a splicing mutation (c.7400+1G>A), which causes exon skipping, were found in multiple subjects that were not known to be related, whereas three other truncating mutations (c.6407del [p.Pro2136Hisfs∗31], c.4804C>T [p.Arg1602∗], and c.7477C>T [p.Arg2493∗]) were identified in single individuals. None of the unaffected first-degree relatives were compound heterozygous for these mutations. Moreover, none of the six putative mutations were detected among 477 French Canadian controls. Our data suggest that mutations in C5ORF42 explain a large portion of French Canadian individuals with JBTS.

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