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

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.

Variants in KIF1A gene in dominant and sporadic forms of hereditary spastic paraparesis

“…Indeed, the S69 residue in the KIF1A motor domain is not the only example for that. Additional KIF1A amino acid residues are now emerging as frequent targets of substitutions such as T99 [6][7][8][9], R216 [8,9], R167 ( [9] and present study), E253, and R316 [8,9], and even among the novel variants here detected, G102 has been found hit twice ( [9] and present study). In fact, G102 undergoes to the p.G102S substitution herein described and to another presumed pathological change (p.G102D) previously reported [9].…”

“…De novo heterozygous dominant variants were found in a wide range of phenotypes as well. A specific mutation p.T99M was found in patients with intellectual disability (ID), spasticity, and axial hypotonia [6] and in another patient with a more severe phenotype including optic atrophy, growth failure, and progressive cerebellar atrophy, in addition to ID and spasticity [7]. A partly overlapping phenotype such as a progressive encephalopathy with brain atrophy was recently found associated with de novo KIF1A mutations [8].…”

De novo, heterozygous, loss‐of‐function mutations in SYNGAP1 cause a syndromic form of intellectual disability

“…Supplementary Table I summarizes the available clinical data on the 26 individuals who have been reported to date with presumed causative mutations in SYNGAP1 or deletions or translocations involving this gene [Hamdan et al, 2009, 2011a, b; Krepischi et al, 2010; Pinto et al, 2010; Vissers et al, 2010; Cook, 2011; Klitten et al, 2011; Zollino et al, 2011; Clement et al, 2012; de Ligt et al, 2012; Rauch et al, 2012; Berryer et al, 2013; Carvill et al, 2013; Writzl and Knegt, 2013; Dyment et al, 2014; O'Roak et al, 2014; Redin et al, 2014]. De novo mutations in this gene are undoubtedly a significant cause of intellectual disability, accounting for 0.62% of all the patients in the DDD Study [Wright et al, 2014] and major contributors to other cohorts that have been studied (Supplementary Table II).…”

“…Heterozygous, de novo loss‐of‐function mutations in SYNGAP1 have been described in 26 individuals to date [Hamdan et al, 2009, 2011a, b; Krepischi et al, 2010; Pinto et al, 2010; Vissers et al, 2010; Zollino et al, 2011; de Ligt et al, 2012; Rauch et al, 2012; Berryer et al, 2013; Carvill et al, 2013; Writzl and Knegt, 2013; Redin et al, 2014]. SYNGAP1 encodes Ras/Rap GTPase‐activating protein SynGAP, which is a major component of the post‐synaptic density that regulates synaptic plasticity and ERK/MAPK signaling probably via N‐methyl‐d‐aspartate (NMDA) receptor activation [Komiyama et al, 2002; Muhia et al, 2010].…”

“…This group subsequently published eight further affected individuals through re‐sequencing predominantly ID cohorts enriched for epilepsy [2011a, b; Berryer et al, 2013]. Carvill et al performed massively parallel sequencing in 500 individuals with epileptic encephalopathy and identified four patients with de novo SYNGAP1 mutations [Carvill et al, 2013].…”