Recessive gene disruptions in autism spectrum disorder

These GEITP pages have often chatted about autism spectrum disorder (ASD) — because it represents a mysterious complex disease that is clearly multifactorial (i.e. the trait represents contribution of genes, epigenetic effects, environmental factors, and perhaps endogenous influences and the gut microbiome). Although the parameters for diagnosing ASD have changed (thereby allowing many more patients to be ‘classified’ today as having ASD), the incidence of the disorder also seems to be increasing dramatically, compared with that of 50 years ago — suggesting environmental contributions (e.g. Western diet, lifestyle, excessive TV- and cell phone-watching, physical inactivity among our young). In the 1960s-70s, for example, I saw only one patient with a definitive diagnosis of ASD (out of perhaps 10,000 patients I had contact with), whereas today the frequency is reported to be as high as one in 60 children. ☹

Genome-wide association studies (GWAS) and whole-genome sequencing (WGS) studies strongly implicate both common variants and

rare de novo variants in ASD. Recessive mutations have also been suggested. Authors [see attached article] performed a systematic analysis of whole-exome sequencing (WES) data from the Autism Sequencing Consortium, representing 2,343 affected and 5,852 unaffected individuals. Authors classified a total of 696,143 autosomal loss-of-function (LOF; ‘autosome’ is any chromosome that is not a sex chromosome) events (representing 28,685 unique variants in 11,745 unique genes) that introduce a stop codon or disrupt a canonical splice site (both of which mess up the mRNA and therefore the protein). After excluding common variants (i.e. allele frequency >1%), there were 84,645 rare LOF events (27,648 unique alleles) for an average of ~10 LOF mutations per individual. After computational phasing, authors found 298 events (after filtering to exclude common variants), which are consistent with complete gene knockouts (homozygous or compound heterozygous LOF mutations), affecting 266 patients.

Affected individuals were disproportionately more likely to harbor a gene knockout (62% more likely compared with unaffected individuals). To control for possible differences in population stratification and family structure (e.g. founder effects and/or consanguinity in the Finnish and Middle Eastern cohorts), authors also normalized to the background burdens of bi-allelic synonymous variants (alteration in a nucleotide but no change in an amino acid). ASD individuals continued to exhibit higher knockout rates after normalization. Based on the observed ascertainment differentials between affected and unaffected individuals, these burdens predict a contribution of bi-allelic LOF alleles to ~1–2% of ASD cases.

Authors documented bi-allelic disruption of known or emerging recessive neurodevelopmental genes (CA2, DDHD1, NSUN2, PAH, RARB, ROGDI, SLC1A1, USH2A) — as well as other genes not previously implicated in ASD — including FEV (FEV transcription factor, ETS family member), which encodes a key regulator of the serotonergic circuitry. These data refine estimates of the contribution of recessive mutations to ASD and suggest new paths for understanding and illuminating previously unknown biological pathways responsible for this complex disease. When the emphasis on “causation of ASD” has almost always been on “polygenic multifactorial inheritance,” here comes a “show-stopper” — a study that reminds us to be humble, i.e. sometimes this very complex disease can be caused by one, or a very small number of, genes. ☹


Nat Genet July 2019; 51: 1092-1105

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