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Title 

Excess of de novo deleterious mutations in genes associated with glutamatergic systems in nonsyndromic intellectual disability

Authors 

F F HamdanJ GauthierY ArakiD T LinY YoshizawaK HigashiA-reum ParkD SpiegelmanS DobrzenieckaA PitonH TomitoriH DaoudC MassicotteE HenrionO DialloM ShekarabiC MarineauM ShevellB MarandaG MitchellA NadeauG D'AnjouM VanasseM SrourR G LafreniereP DrapeauJ C LacailleE KimJae-Ran LeeK IgarashiR L HuganirG A RouleauJ L Michaud

Publisher 

Elsevier

Issue Date 

2011

Citation 

American Journal of Human Genetics, vol. 88, no. 3, pp. 306-316

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.

ISSN 

0002-9297

Link 

http://dx.doi.org/10.1016/j.ajhg.2011.02.001

Appears in Collections

1. Journal Articles > Journal Articles

Registered Date

2017-04-19


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