Meta-analysis of 2,104 trios provides support for 10 new genes for intellectual disability

Abstract

To identify candidate genes for intellectual disability, we performed a meta-analysis on 2,637 de novo mutations, identified from the exomes of 2,104 patient-parent trios. Statistical analyses identified 10 new candidate ID genes: DLG4, PPM1D, RAC1, SMAD6, SON, SOX5, SYNCRIP, TCF20, TLK2 and TRIP12. In addition, we show that these genes are intolerant to nonsynonymous variation and that mutations in these genes are associated with specific clinical ID phenotypes.

Loss-of-Function and Gain-of-Function Mutations in KCNQ5 Cause Intellectual Disability or Epileptic Encephalopathy

“…Sleep disturbance affects individuals 1 and 2. We searched previously published datasets of largescale sequencing studies on the causes of neurodevelopmental disability for other reports of de novo KCNQ5 mutations and found c.867G>T (p.Lys289Asn), c.1328G>A (p.Arg443Gln), and c.1727A>G (p.His576Arg) in the supplemental data from 820 probands in Lelieveld et al 17 However, these variants were not identified as candidate causes of neurodevelopmental disability in the course of the authors' statistical analyses. The largest currently published cohort of individuals with developmental disorders (the Deciphering Developmental Disorders study, n ¼ 4,293) did not feature any KCNQ5 de novo variants, 18 nor were any included in the data from the cohort of 2,508 autism probands from Iossifov et al 19 Because of the above evidence associating KCNQ5 mutations with neurodevelopmental disorders, as well as prior evidence that mutations in KCNQ2 (encoding Kv7.2) and KCNQ3 (encoding Kv7.3) most likely cause neurological disease via reduced basal M-current (and subsequent neuronal hyperexcitability), 20 the impact of each mutation was characterized in vitro.…”

Spatial Clustering of de Novo Missense Mutations Identifies Candidate Neurodevelopmental Disorder-Associated Genes

“…In addition, we added 1,183 de novo variants identified in the exomes of an in-house ID cohort that was previously published. 8 To further reduce the risk of including sequencing artifacts and/or genotyping errors, we excluded all de novo variants that were present more than once in the ExAC dataset (Table S1). 15 These efforts resulted in 6,495 protein coding DNMs, including 4,061 missense mutations, in 5,302 individuals with ID/DD (Table S2).…”

“…[3][4][5][6] Similarly, largescale WES studies of individuals affected by ID/DD have recently leveraged this phenomenon as supporting evidence of the involvement of a gene in disease. 7,8 This spatial clustering of de novo mutations (DNMs) is typical for missense mutations in genes without clear, or limited numbers of, truncating mutations subsequently degraded by nonsense-mediated mRNA decay, suggesting that these clustered mutations act through a different mechanism than haploinsufficiency (HI). 9 Alternative pathophysiological mechanisms that might underlie (de novo) mutation clustering are gain-of-function or dominant-negative effects, resulting in the alteration or impairment of specific protein function.…”

“…In this cohort, we failed to identify genes for which clustering of de novo missense mutations reached statistical significance (Table S4). However, application of our method to the dataset of 4,061 DNMs, containing 583 genes with more than one de novo missense mutation, revealed 15 genes with significant clustering 7,8,[23][24][25] (Table 1, Figure 1, Figures S1-S15). In these genes, a total of 107 de novo missense mutations contributed to mutation clustering, ranging from three to 20 mutations per gene with an average distance ranging from 0 to 354 bp.…”

RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes

“…3 Recently, large-scale next generation sequencing studies have led to the identification of several DD-associated genes that lead to clinical manifestations through protein truncating or recurrent missense variants. [4][5][6] However, rare disorders caused by private, non-recurrent missense mutations that result in varying phenotypes remain challenging to dissect. 7 Several human DDs are known to result from mutations in members of the RAS superfamily of small GTPases.…”