Identifying Autism Loci and Genes by Tracing Recent Shared Ancestry

TLDR

The study aimed to identify inherited causes of autism‑spectrum disorders. Researchers examined families whose parents share recent common ancestors to increase the influence of inherited factors. They mapped multiple loci with large homozygous deletions, pinpointing genes such as PCDH10, DIA1, and NHE9, and demonstrated that disrupted activity‑dependent gene regulation may be a shared mechanism underlying diverse autism mutations, underscoring the value of homozygosity mapping.

Abstract

To find inherited causes of autism-spectrum disorders, we studied families in which parents share ancestors, enhancing the role of inherited factors. We mapped several loci, some containing large, inherited, homozygous deletions that are likely mutations. The largest deletions implicated genes, including PCDH10 (protocadherin 10) and DIA1 (deleted in autism1, or c3orf58), whose level of expression changes in response to neuronal activity, a marker of genes involved in synaptic changes that underlie learning. A subset of genes, including NHE9 (Na+/H+ exchanger 9), showed additional potential mutations in patients with unrelated parents. Our findings highlight the utility of "homozygosity mapping" in heterogeneous disorders like autism but also suggest that defective regulation of gene expression after neural activity may be a mechanism common to seemingly diverse autism mutations.