Genome-wide characteristics of de novo mutations in autism

Abstract

De novo mutations (DNMs) are important in autism spectrum disorder (ASD), but so far analyses have mainly been on the ~1.5% of the genome encoding genes. Here, we performed whole-genome sequencing (WGS) of 200 ASD parent–child trios and characterised germline and somatic DNMs. We confirmed that the majority of germline DNMs (75.6%) originated from the father, and these increased significantly with paternal age only (P=4.2×10−10). However, when clustered DNMs (those within 20 kb) were found in ASD, not only did they mostly originate from the mother (P=7.7×10−13), but they could also be found adjacent to de novo copy number variations where the mutation rate was significantly elevated (P=2.4×10−24). By comparing with DNMs detected in controls, we found a significant enrichment of predicted damaging DNMs in ASD cases (P=8.0×10−9; odds ratio=1.84), of which 15.6% (P=4.3×10−3) and 22.5% (P=7.0×10−5) were non-coding or genic non-coding, respectively. The non-coding elements most enriched for DNM were untranslated regions of genes, regulatory sequences involved in exon-skipping and DNase I hypersensitive regions. Using microarrays and a novel outlier detection test, we also found aberrant methylation profiles in 2/185 (1.1%) of ASD cases. These same individuals carried independently identified DNMs in the ASD-risk and epigenetic genes DNMT3A and ADNP. Our data begins to characterize different genome-wide DNMs, and highlight the contribution of non-coding variants, to the aetiology of ASD.

The Genetic and Epigenetic Basis Involved in the Pathophysiology of ASD: Therapeutic Implications

“…Epigenetic state in ASD, mainly epigenetic mark of DNA CpG methylation, can be used as biomarker of disease risk, diagnosis, prognosis, and response to treatments; but also, clues to the causal factors and mechanisms of the disorder [105]. So, aberrant methylation profiles in 1.1% of ASD cases have been reported [13]. A significant overrepresentation of genes with functions in chromatin regulation and early developmental expression was found in ASD probands but not in unaffected siblings [106].…”

“…So, nowadays attention has turned to environmental factors but also with epigenetic changes as potential etiological agents predisposing to autism susceptibility. New genetics analyses have displayed a multitude of novel candidate ASD-genes in networks that involve epigenetic change, encoding nuclear factors implicated in chromatin remodeling, histone demethylation, histone variants, and the recognition of DNA methylation [13,108]. This approach is described as an "epigenome-wide association study" (EWAS) and takes its cue from the association of genetic variability with phenotypes in GWAS.…”

“…Today, different studies support that the etiopathogenesis of ADS involves an interaction between both susceptible genetic loci and a wide range of environmental risk factors on the developmental trajectory. So the pathogenesis of ASD is considered an authentic "puzzle," for a multifactorial threshold model underlying ASD with all types of genetic variation (SNV/indel/CNV in coding and noncoding DNA, germline, somatic, epigenetic) and environmental factors (the most significant: toxic, immune dysregulation, and nutritional status) involved in clinical, neuropsychological, and neurobiological perspectives [13,[15][16][17][18].…”

“…Classically in DSM IV-TR [1] "Pervasive developmental disorders" (PDD) encompass a heterogeneous group of children characterized by severe and pervasive impairment in several areas of development: (1) reciprocal social interaction skills, (2) communication skills, and (3) the presence of stereotyped behavior, interests, and activities. The qualitative impairments that define these conditions are distinctly deviant relative to the individual's developmental Because people with autism can have very different features and symptoms with very high degree of phenotypic heterogeneity, autism is a multifactorial condition and is thought of as a spectrum disorder [12,13]. Autism is one of the most complex heritable disorders, and a paradigmatic complex genetic disorder, with convincing evidence for genetic factors and little or no support for the influence of the environment factors [14].…”

APOBEC3A/B-induced mutagenesis is responsible for 20% of heritable mutations in the TpCpW context

“…Recent studies have shown that different numbers of de novo mutations are inherited from the father and from the mother, with the contribution of paternal mutations being two to four times higher (Kong et al 2012;Francioli et al 2015;Wong et al 2016;Yuen et al 2016). Additionally, the number of de novo mutations strongly depends on the father's age at conception (Kong et al 2012;Francioli et al 2015;Wong et al 2016;Yuen et al 2016) and, to a lesser extent, on the mother's age at conception (Goldmann et al 2016;Wong et al 2016). At the molecular level, the understanding of mechanisms of heritable mutagenesis is very limited.…”