Genome-wide detection of tandem DNA repeats that are expanded in autism

Tandem DNA repeats vary by the size and sequence of each unit (motif). When expanded, they have been associated with more than 40 monogenic disorders1. Their involvement in complex disorders is largely unknown, as is the extent of their heterogeneity. Here, we interrogated genome-wide characteristics of tandem repeats with 2–20-bp motifs in 17,231 genomes of families with autism2,3 and population controls4. We found extensive polymorphism in motif size and sequence. Many correlated with cytogenetic fragile sites. At 2,588 loci, gene-associated tandem repeat expansions that were rare among population controls were significantly more prevalent among individuals with autism than their unaffected siblings, particularly in exons and near splice junctions and in genes related to nervous system development and cardiovascular system or muscle. Rare tandem repeat expansions had a prevalence of 23.3% in autism-affected children versus 20.7% in unaffected children, suggesting a collective contribution to autism risk of 2.6%. They included novel autism-linked tandem repeat expansions in DMPK and FXN, known for neuromuscular conditions, and in novel loci such as FGF14 and CACNB1. These were associated with lower IQ and adaptive ability. Our results revealed a strong contribution of tandem DNA repeat expansions to the genetic etiology and phenotypic complexity of autism.