Intellectual Disability Is Associated with Increased Runs of Homozygosity in Simplex Autism

Intellectual disability(ID), often attributed to autosomal-recessive mutations, occurs in 40% of autismspectrum disorders (ASDs). For this reason, we conducted a genome-wide analysis of runsof homozygosity(ROH) in simplex ASD-affected families consisting of a probanddiagnosed with ASD and at least one unaffected sibling. In these families, probandswith an IQ ≤ 70 show more ROH than their unaffected siblings, whereas probandswith an IQ > 70 do not show this excess. Although ASD is far more common in males than in females, the proportion of females increases with decreasing IQ. Our data do supportan association between ROH burden and autismdiagnosis in girls; however, we are not able to show that this effect is independent of low IQ. We have also discovered several autismcandidate genes on the basis of finding (1) a single gene that is within an ROH interval and that is recurrent in autismor (2) a gene that is within an autismROH block and that harbors a homozygous, rare deleterious variant upon analysis of exome-sequencing data. In summary, our data suggest a distinct genetic architecturefor participants with autismand co-occurring intellectual disabilityand that this architecture could involve a role for recessively inherited loci for this autismsubgroup.