Sporadic autism exomes reveal a highly interconnected protein network of de novo mutations

Abstract

It is well established that autism spectrum disorders (ASD) have a strong genetic component. However, for at least 70% of cases, the underlying genetic cause is unknown1. Under the hypothesis that de novo mutations underlie a substantial fraction of the risk for developing ASD in families with no previous history of ASD or related phenotypes—so-called sporadic or simplex families2,3, we sequenced all coding regions of the genome, i.e. the exome, for parent-child trios exhibiting sporadic ASD, including 189 new trios and 20 previously reported4. Additionally, we also sequenced the exomes of 50 unaffected siblings corresponding to these new (n = 31) and previously reported trios (n = 19)4, for a total of 677 individual exomes from 209 families. Here we show de novo point mutations are overwhelmingly paternal in origin (4:1 bias) and positively correlated with paternal age, consistent with the modest increased risk for children of older fathers to develop ASD5. Moreover, 39% (49/126) of the most severe or disruptive de novo mutations map to a highly interconnected beta-catenin/chromatin remodeling protein network ranked significantly for autism candidate genes. In proband exomes, recurrent protein-altering mutations were observed in two genes, CHD8 and NTNG1. Mutation screening of six candidate genes in 1,703 ASD probands identified additional de novo, protein-altering mutations in GRIN2B, LAMC3, and SCN1A. Combined with copy number variant (CNV) data, these results suggest extreme locus heterogeneity but also provide a target for future discovery, diagnostics, and therapeutics.

The Immune Signaling Adaptor LAT Contributes to the Neuroanatomical Phenotype of 16p11.2 BP2-BP3 CNVs

“…Consistent with this view, the genes differentially expressed in cell lines of 16p11.2 600 kb BP4-BP5 carriers were enriched not only in pathways relevant to neurodevelopmental defects and ciliopathy but also in genes involved in phosphoinositide signaling. 22 Of note, germline variants in PTEN present the ASD, obesity, and macrocephaly triad of phenotypes, [66][67][68][69][70] whereas those in the Ras/MAPK signaling pathway are associated with social impairment. 71 The interactions observed at this cluster of genes, both at the chromatin and genetic level, suggest that the CNVprone non-overlapping loci at 16p11.2 should be approached and studied as ''connected regions'' rather than completely independent entities.…”

Autism throughout genetics: Perusal of the implication of ion channels

“…Besides structural rearrangements, other abnormalities of chromosomal numbers or aneuploidies are detected in ASD including trisomy 21, Turner syndrome (45, X), and Klinefelter syndrome (47, XXY; Devlin & Scherer, 2012). Thanks to the comparative genomic hybridization (CGH) technique or SNPs array, CNVs were also found in multiple chromosomal regions at 1q21.1, 16p11.2, 17q12, and 22q11.2 (Jacquemont et al., 2006; Marshall et al., 2008; Matsunami et al., 2013; O'Roak et al., 2012; Pinto et al., 2010; Sebat et al., 2007). Further studies supported the association with ASD of two recurrent de novo CNVs at 16p11.2 (duplication and deletion) and 7q11.23 (duplication; Levy et al., 2011; Sanders Stephan et al., 2011).…”

“…A chromosomal translocation of 2p:12p resulting in a deletion of both genes ( CACNA1C and CACNA2D4 ) was detected in two ASD‐affected individuals (Smith et al., 2012). Furthermore, a whole‐exome sequencing study identified de novo rare alleles in α 1 subunit loci CACNA1D and CACNA1E (O'Roak et al., 2012; Pinggera et al., 2015). The α 1 subunit (Ca v 1.3) of L‐type channels plays an important role in neuronal signaling and in brain function including memory and behavior (Pinggera et al., 2015).…”

“…Another study using array‐comparative genome hybridization identified a de novo deletion in a chromosome 2 region (2q24.2–q24.3) that contains SCN2A and SCN3A genes in a child with ASD (Celle, Cuoco, Porta, Gimelli, & Tassano, 2013). These findings were also validated by whole‐exome sequencing study showing a significant association of SCN1A gene with the etiology of ASD (O'Roak et al., 2012; Sanders et al., 2012). Tavassoli et al.…”

Prospective diagnostic analysis of copy number variants using SNP microarrays in individuals with autism spectrum disorders

“…1,2 Recent studies have demonstrated that ASDs can be caused by rare, highly penetrant point mutations, deletions, duplications and larger chromosomal abnormalities that can either arise de novo or be inherited. [3][4][5][6][7][8][9] Known monogenic disorders account for 2-5% of syndromic cases; fragile X syndrome is usually the most common cause, followed by PTEN macrocephaly syndrome and tuberous sclerosis, each accounting for o1% of individuals with ASD. 1,10 Large copy number variants (CNVs) are found in 5-10% of autistic patients, especially in those with syndromic ASDs.…”