期刊
NEURON
卷 77, 期 2, 页码 259-273出版社
CELL PRESS
DOI: 10.1016/j.neuron.2012.11.002
关键词
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资金
- National Institute of Mental Health (NIMH)
- National Institute of Health (NIH) [T32 NS007484-08, T32 N5007473-12]
- Clinical Investigator Training Program (CITP) at Harvard-MIT Health Sciences and Technology
- Beth Israel Deaconess Medical Center
- Pfizer, Inc.
- Merck and Company, Inc.
- Nancy Lurie Marks Junior Faculty MeRIT Fellowship
- NARSAD
- National Institutes of Neurological Disease and Stroke [K23NS069784]
- National Institute of General Medical Sciences [T32GM07753]
- National Institute of Mental Health [RO1 MH083565, 1RC2MH089952]
- NIH [RO1 N5048276]
- NIMH [1K23MH080954-01]
- Dubai Harvard Foundation for Medical Research
- Nancy Lurie Marks Foundation
- Simons Foundation
- Autism Consortium
- Manton Center for Orphan Disease Research
- ARRA Grand Opportunities [1RC2MH089952]
Despite significant heritability of autism spectrum disorders (ASDs), their extreme genetic heterogeneity has proven challenging for gene discovery. Studies of primarily simplex families have implicated de novo copy number changes and point mutations, but are not optimally designed to identify inherited risk alleles. We apply whole-exome sequencing (WES) to ASD families enriched for inherited causes due to consanguinity and find familial ASD associated with biallelic mutations in disease genes (AMT, PEX7, SYNE1, VPS13B, PAH, and POMGNT1). At least some of these genes show biallelic mutations in nonconsanguineous families as well. These mutations are often only partially disabling or present atypically, with patients lacking diagnostic features of the Mendelian disorders with which these genes are classically associated. Our study shows the utility of WES for identifying specific genetic conditions not clinically suspected and the importance of partial loss of gene function in ASDs.
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