NEW YORK (GenomeWeb) – A team led by investigators in the US, France, Germany, and the UK has identified recessive changes — altering both copies of the affected genes — in a subset of individuals with autism spectrum disorder (ASD), particularly in ASD cases occurring in females.
"Our data refine estimates of the contribution of recessive mutation to ASD and suggest new paths for illuminating previously unknown biological pathways responsible for this condition," senior author Timothy Yu, a genetics and genomics researcher affiliated with Boston Children's Hospital, Harvard Medical School, and the Broad, and his co-authors wrote.
Using exome sequences for thousands of ASD cases and controls profiled by the Autism Sequencing Consortium, Yu and his colleagues searched for biallelic loss-of function alterations or missense mutations impacting both alleles of a given gene. Such changes turned up in roughly 5 percent of ASD cases profiled overall, but were found in some 10 percent of female individuals with ASD.
Past studies have pointed to a so-called "female protective/male susceptibility effect" in ASD, the team explained. The group of neurodevelopmental conditions categorized as ASD are more common in males, and when they do occur in females, affected girls and women typically carry more de novo variants, inherited risk variants, and/or copy number changes than their male counterparts.
"Our study extends prior estimates of the contribution of recessive mutations to ASD and proves that the female protective/male susceptibility effect in ASD also applies to biallelic mutations," the authors wrote. "Expanding these efforts to larger ASD cohorts should offer a path forward to delineate previously unknown neurobiological mechanisms in autism."
The team published its findings online today in Nature Genetics.
For their analysis, the investigators pulled together exome sequences for 2,343 individuals with ASD and 5,862 without, identifying hundreds of thousands of autosomal loss-of-function events involving nearly 28,700 variants in 11,745 genes. They narrowed that set down to 84,645 rare, recessive, loss-of-function events involving 27,648 alleles by tossing out more common variants with allele frequencies exceeding 1 percent.
Those rare, recessive, loss-of-function, or "gene knockout," events were found more frequently in the ASD cases compared to controls, the team reported, even after accounting for participants' population and family structure.
In particular, the investigators identified 298 gene knockout events affecting 237 genes in 266 of the ASD cases. When they broadened the analysis to include hundreds more genes marked by damaging missense mutations, they again saw an over-representation of the rare, recessive changes in individuals with ASD — an effect that was especially pronounced in the female cases and in individuals with ASD who did not carry ASD-related de novo loss-of-function mutations.
The team noted that these recessive changes often occurred in genes such as CA1, DDHD1, and NSUN2 from neurodevelopmental pathways, as well as other genes implicated in ASD in the past. It also picked up a previously unreported association between ASD and biallelic mutations affecting an ETS family transcription factor gene called FEV.
"Two brothers with ASD bore homozygous stop-gain mutations in FEV," the authors reported, "which encodes a transcription factor that is required for both the development and function of serotonergic neurons."