Publication Date:
2012-04-13
Description:
Multiple studies have confirmed the contribution of rare de novo copy number variations to the risk for autism spectrum disorders. But whereas de novo single nucleotide variants have been identified in affected individuals, their contribution to risk has yet to be clarified. Specifically, the frequency and distribution of these mutations have not been well characterized in matched unaffected controls, and such data are vital to the interpretation of de novo coding mutations observed in probands. Here we show, using whole-exome sequencing of 928 individuals, including 200 phenotypically discordant sibling pairs, that highly disruptive (nonsense and splice-site) de novo mutations in brain-expressed genes are associated with autism spectrum disorders and carry large effects. On the basis of mutation rates in unaffected individuals, we demonstrate that multiple independent de novo single nucleotide variants in the same gene among unrelated probands reliably identifies risk alleles, providing a clear path forward for gene discovery. Among a total of 279 identified de novo coding mutations, there is a single instance in probands, and none in siblings, in which two independent nonsense variants disrupt the same gene, SCN2A (sodium channel, voltage-gated, type II, alpha subunit), a result that is highly unlikely by chance.〈br /〉〈br /〉〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3667984/" target="_blank"〉〈img src="https://static.pubmed.gov/portal/portal3rc.fcgi/4089621/img/3977009" border="0"〉〈/a〉 〈a href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3667984/" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Sanders, Stephan J -- Murtha, Michael T -- Gupta, Abha R -- Murdoch, John D -- Raubeson, Melanie J -- Willsey, A Jeremy -- Ercan-Sencicek, A Gulhan -- DiLullo, Nicholas M -- Parikshak, Neelroop N -- Stein, Jason L -- Walker, Michael F -- Ober, Gordon T -- Teran, Nicole A -- Song, Youeun -- El-Fishawy, Paul -- Murtha, Ryan C -- Choi, Murim -- Overton, John D -- Bjornson, Robert D -- Carriero, Nicholas J -- Meyer, Kyle A -- Bilguvar, Kaya -- Mane, Shrikant M -- Sestan, Nenad -- Lifton, Richard P -- Gunel, Murat -- Roeder, Kathryn -- Geschwind, Daniel H -- Devlin, Bernie -- State, Matthew W -- K08 MH087639/MH/NIMH NIH HHS/ -- R25 MH077823/MH/NIMH NIH HHS/ -- T32 GM008042/GM/NIGMS NIH HHS/ -- U01 MH081896/MH/NIMH NIH HHS/ -- Howard Hughes Medical Institute/ -- England -- Nature. 2012 Apr 4;485(7397):237-41. doi: 10.1038/nature10945.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Program on Neurogenetics, Child Study Center, Department of Psychiatry, Yale University School of Medicine, 230 South Frontage Road, New Haven, Connecticut 06520, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="http://www.ncbi.nlm.nih.gov/pubmed/22495306" target="_blank"〉PubMed〈/a〉
Keywords:
Alleles
;
Autistic Disorder/*genetics
;
Codon, Nonsense/genetics
;
Exome/*genetics
;
Exons/*genetics
;
Genetic Heterogeneity
;
Genetic Predisposition to Disease/*genetics
;
Humans
;
Mutation/*genetics
;
NAV1.2 Voltage-Gated Sodium Channel
;
Nerve Tissue Proteins/*genetics
;
RNA Splice Sites/genetics
;
Siblings
;
Sodium Channels/*genetics
Print ISSN:
0028-0836
Electronic ISSN:
1476-4687
Topics:
Biology
,
Chemistry and Pharmacology
,
Medicine
,
Natural Sciences in General
,
Physics
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