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Title: | Refining analyses of copy number variation identifies specific genes associated with developmental delay. | Austin Authors: | Coe, Bradley P;Witherspoon, Kali;Rosenfeld, Jill A;van Bon, Bregje W M;Vulto-van Silfhout, Anneke T;Bosco, Paolo;Friend, Kathryn L;Baker, Carl;Buono, Serafino;Vissers, Lisenka E L M;Schuurs-Hoeijmakers, Janneke H;Hoischen, Alex;Pfundt, Rolph;Krumm, Nik;Carvill, Gemma L;Li, Deana;Amaral, David;Brown, Natasha;Lockhart, Paul J;Scheffer, Ingrid E ;Alberti, Antonino;Shaw, Marie;Pettinato, Rosa;Tervo, Raymond;de Leeuw, Nicole;Reijnders, Margot R F;Torchia, Beth S;Peeters, Hilde;O'Roak, Brian J;Fichera, Marco;Hehir-Kwa, Jayne Y;Shendure, Jay;Mefford, Heather C;Haan, Eric;Gécz, Jozef;de Vries, Bert B A;Romano, Corrado;Eichler, Evan E | Affiliation: | Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands. Department of Paediatrics, University of Melbourne, Royal Children's Hospital, Melbourne, Victoria, Australia Leuven Autism Research (LAuRes), Leuven, Belgium. Center for Human Genetics, University Hospitals Leuven, KU Leuven, Leuven, Belgium. SA Pathology, North Adelaide, South Australia, Australia Barwon Child Health Unit, Barwon Health, Geelong, Victoria, Australia Murdoch Childrens Research Institute, University of Melbourne, Royal Children's Hospital, Melbourne, Victoria, Australia Florey Institute, University of Melbourne, Austin Health and Royal Children's Hospital, Melbourne, Victoria, Australia SA Pathology, North Adelaide, South Australia, Australia Robinson Institute, University of Adelaide, Adelaide, South Australia, Australia IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Associazione Oasi Maria Santissima, Troina, Italy. Howard Hughes Medical Institute, Seattle, Washington, USA Signature Genomics Laboratories, LLC, PerkinElmer, Inc., Spokane, Washington, USA SA Pathology, North Adelaide, South Australia, Australia Department of Pediatrics, University of Washington, Seattle, Washington, USA Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA Division of Developmental and Behavioral Pediatrics, Mayo Clinic, Rochester, Minnesota, USA Representing the Autism Phenome Project, MIND Institute, University of California, Davis, Sacramento, California, USA School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, South Australia, Australia Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands. IRCCS (Istituto di Ricovero e Cura a Carattere Scientifico) Associazione Oasi Maria Santissima, Troina, Italy. |
Issue Date: | 14-Sep-2014 | Publication information: | Nature Genetics 2014; 46(10): 1063-71 | Abstract: | Copy number variants (CNVs) are associated with many neurocognitive disorders; however, these events are typically large, and the underlying causative genes are unclear. We created an expanded CNV morbidity map from 29,085 children with developmental delay in comparison to 19,584 healthy controls, identifying 70 significant CNVs. We resequenced 26 candidate genes in 4,716 additional cases with developmental delay or autism and 2,193 controls. An integrated analysis of CNV and single-nucleotide variant (SNV) data pinpointed 10 genes enriched for putative loss of function. Follow-up of a subset of affected individuals identified new clinical subtypes of pediatric disease and the genes responsible for disease-associated CNVs. These genetic changes include haploinsufficiency of SETBP1 associated with intellectual disability and loss of expressive language and truncations of ZMYND11 in individuals with autism, aggression and complex neuropsychiatric features. This combined CNV and SNV approach facilitates the rapid discovery of new syndromes and genes involved in neuropsychiatric disease despite extensive genetic heterogeneity. | Gov't Doc #: | 25217958 | URI: | https://ahro.austin.org.au/austinjspui/handle/1/12389 | DOI: | 10.1038/ng.3092 | Journal: | Nature genetics | URL: | https://pubmed.ncbi.nlm.nih.gov/25217958 | Type: | Journal Article | Subjects: | Autistic Disorder.genetics Base Sequence Carrier Proteins.genetics Child Chromosome Mapping Comparative Genomic Hybridization DNA Copy Number Variations Developmental Disabilities.genetics Female Genetic Association Studies Genetic Predisposition to Disease.genetics Haploinsufficiency.genetics Humans Intellectual Disability.genetics Male Molecular Sequence Data Nuclear Proteins.genetics Polymorphism, Single Nucleotide Sequence Analysis, DNA |
Appears in Collections: | Journal articles |
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