Excess of De Novo Deleterious Mutations in Genes Associated with Glutamatergic Systems in Nonsyndromic Intellectual Disability

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• 作者：Fadi  ; F. Hamdan¹ ; Julie Gauthier² ; Yoichi Araki³ ; Da-Ting Lin³ ; Yuhki Yoshizawa⁴ ; Kyohei Higashi⁴ ; A-Reum Park⁵ ; Dan Spiegelman² ; Sylvia Dobrzeniecka² ; Am&#xe9 ; lie Piton² ; Hideyuki Tomitori⁴ ; Hussein Daoud² ; Christine Massicotte¹ ; Edouard Henrion² ; Ousmane Diallo² ; S2D Group² ; Masoud Shekarabi² ; Claude Marineau² ; Michael Shevell⁶ ; Bruno Maranda⁷ ; Grant Mitchell¹ ; Am&#xe9 ; lie Nadeau¹ ; Guy D'Anjou¹ ; Michel Vanasse¹ ; Myriam Srour¹ ; Ronald  ; G. Lafreni&#xe8 ; re² ; Pierre Drapeau⁸ ; Jean  ; Claude Lacaille⁹ ; Eunjoon Kim¹⁰ ; Jae-Ran Lee⁵ ; Kazuei Igarashi⁴ ; Richard  ; L. Huganir³ ; Guy  ; A. Rouleau² ; Jacques  ; L. Michaud¹ ; ^{jacques.michaud@recherche-ste-justine.qc.ca}
• 刊名：The American Journal of Human Genetics
• 出版年：2011
• 出版时间：11 March 2011
• 年：2011
• 卷：88
• 期：3
• 页码：306-316
• 全文大小：981 K

文摘

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.