To sort the genetic heterogeneity of autism, we used homozygosity analysis [19] to identify a subset of patients likely to be enriched for recessive mutations. We performed a homozygosity-based analysis of 1000 families (5,431 individuals) in the Autism Genetic Research Exchange (AGRE) [20] cohort. Though most American families in this cohort are of mixed European ancestry and share no acknowledged near ancestors, we hypothesized that a small proportion of European-American parents share a traceable common ancestor, or may share common ethnic ancestry through both parental lines, which in either case may result in homozygosity for rare recessive founder mutations, as has been demonstrated for a host of known Mendelian recessive diseases [21]. We identified a small subset of “outlier” AGRE families (<2% of the total) in which the affected children show runs of homozygosity totaling up to ∼9% of their genome. This low proportion of families with elevated homozygosity is consistent with low reported rates of consanguinity in the AGRE collection. Nonetheless, in the few outlier families, rates of homozygosity are far higher than generally observed in individuals whose parents
