Assessment of 2q23.1 microdeletion syndrome implicates MBD5 as a single causal locus of intellectual disability, epilepsy, and autism spectrum disorder |
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| Authors: | Talkowski Michael E Mullegama Sureni V Rosenfeld Jill A van Bon Bregje W M Shen Yiping Repnikova Elena A Gastier-Foster Julie Thrush Devon Lamb Kathiresan Sekar Ruderfer Douglas M Chiang Colby Hanscom Carrie Ernst Carl Lindgren Amelia M Morton Cynthia C An Yu Astbury Caroline Brueton Louise A Lichtenbelt Klaske D Ades Lesley C Fichera Marco Romano Corrado Innis Jeffrey W Williams Charles A Bartholomew Dennis Van Allen Margot I Parikh Aditi Zhang Lilei Wu Bai-Lin Pyatt Robert E Schwartz Stuart Shaffer Lisa G de Vries Bert B A Gusella James F Elsea Sarah H |
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| Affiliation: | 1Center for Human Genetic Research, Massachusetts General Hospital, Boston, MA 02114, USA;2Departments of Genetics and Neurology, Harvard Medical School, Harvard University, Cambridge, MA 02115, USA;3Program in Medical and Population Genetics, Broad Institute, Cambridge, MA 02143, USA;4Department of Human and Molecular Genetics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA;5Signature Genomic Laboratories, PerkinElmer Inc, Spokane, WA 99207, USA;6Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen 6525 GA, The Netherlands;7Shanghai Children's Medical Center, Jiaotong University School of Medicine, 200127 Shanghai, China;8Departments of Laboratory Medicine and Pathology, Children's Hospital Boston and Harvard Medical School, Boston, MA 02115, USA;9Department of Pathology and Laboratory Medicine, Nationwide Children's Hospital, Columbus, OH 43205, USA;10Department of Pathology, The Ohio State University, Columbus, OH 43210, USA;11Department of Pediatrics, The Ohio State University, Columbus, OH 43210, USA;12Cardiovascular Research Center, Massachusetts General Hospital, Boston, MA 02114, USA;13Department of Medicine, Harvard Medical School, Boston, MA 02115, USA;14Psychiatric and Neurodevelopmental Genetics Unit, Department of Psychiatry, Massachusetts General Hospital and Harvard Medical School, Boston, MA 02114, USA;15Stanley Center for Psychiatric Research, Broad Institute, Cambridge, MA 02143, USA;16Department of Obstetrics, Gynecology and Reproductive Biology, and Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA;17Children's Hospital and Institutes of Biomedical Science, Fudan University, 200032 Shanghai, China;18West Midlands Region Genetics Service, Clinical Genetics Unit, Birmingham Women's Hospital, Edgbaston, Birmingham, West Midlands B15 2TG, UK;19Department of Medical Genetics, University Medical Centre Utrecht, Utrecht 3584 CX, The Netherlands;20Discipline of Paediatrics and Child Health, University of Sydney, Sydney, NSW 2006, Australia;21Laboratory of Genetic Diagnosis, Istituto Di Ricovero e Cura a Carattere Scientifico (IRCCS) Associazione Oasi Maria Santissima, Troina 94018, Italy;22Pediatrics and Medical Genetics, IRCCS, Associazione Oasi Maria Santissima, Troina 94108, Italy;23Departments of Human Genetics and Pediatrics and Communicable Diseases, University of Michigan, Ann Arbor, MI 48109, USA;24Division of Genetics and Metabolism, Department of Pediatrics, University of Florida College of Medicine, Gainesville, FL 32611, USA;25Division of Molecular and Human Genetics, Nationwide Children's Hospital, Columbus, OH 43205, USA;26Department of Medical Genetics, University of British Columbia, Vancouver, BC V6H 3N1, Canada;27Department of Pediatrics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA;28Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA;29LabCorp, Research Triangle Park, NC 27709, USA;30Department of Pediatrics, Virginia Commonwealth University School of Medicine, Richmond, VA 23298, USA |
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| Abstract: | Persons with neurodevelopmental disorders or autism spectrum disorder (ASD) often harbor chromosomal microdeletions, yet the individual genetic contributors within these regions have not been systematically evaluated. We established a consortium of clinical diagnostic and research laboratories to accumulate a large cohort with genetic alterations of chromosomal region 2q23.1 and acquired 65 subjects with microdeletion or translocation. We sequenced translocation breakpoints; aligned microdeletions to determine the critical region; assessed effects on mRNA expression; and examined medical records, photos, and clinical evaluations. We identified a single gene, methyl-CpG-binding domain 5 (MBD5), as the only locus that defined the critical region. Partial or complete deletion of MBD5 was associated with haploinsufficiency of mRNA expression, intellectual disability, epilepsy, and autistic features. Fourteen alterations, including partial deletions of noncoding regions not typically captured or considered pathogenic by current diagnostic screening, disrupted MBD5 alone. Expression profiles and clinical characteristics were largely indistinguishable between MBD5-specific alteration and deletion of the entire 2q23.1 interval. No copy-number alterations of MBD5 were observed in 7878 controls, suggesting MBD5 alterations are highly penetrant. We surveyed MBD5 coding variations among 747 ASD subjects compared to 2043 non-ASD subjects analyzed by whole-exome sequencing and detected an association with a highly conserved methyl-CpG-binding domain missense variant, p.79Gly>Glu (c.236G>A) (p = 0.012). These results suggest that genetic alterations of MBD5 cause features of 2q23.1 microdeletion syndrome and that this epigenetic regulator significantly contributes to ASD risk, warranting further consideration in research and clinical diagnostic screening and highlighting the importance of chromatin remodeling in the etiology of these complex disorders. |
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