Tandem Repeat Expansions in Autism Spectrum Disorder: From Discovery to Therapeutic Opportunities

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Abstract
Autism spectrum disorder (ASD) is a highly heritable and heterogeneous neurodevelopmental condition for which currently identified genetic variants explain only a subset of cases. Tandem repeat expansions (TREs) have recently emerged as an underappreciated source of genetic risk for ASD and other complex disorders. Advances in genome sequencing technologies, from short-read to long-read platforms, have substantially expanded the discovery of TREs and their contribution to ASD-risk, implicating their involvement in ASD etiology. In this review, we summarize recent advances in the genetics of ASD and discuss how the molecular mechanisms of established TREs provide mechanistic insights into ASD biology. We highlight the FMR1 CGG and DMPK CTG repeat expansions, which, through distinct pathogenic mechanisms, contribute to the high prevalence of ASD in fragile X syndrome and congenital myotonic dystrophy type 1, respectively. Emerging evidence suggests that disruption of post-transcriptional gene regulation, particularly developmental RNA splicing, may represent a convergent pathway across syndromic and idiopathic ASD. Finally, we discuss the emerging therapeutic strategies and consider how advances in TRE disease biology may facilitate further development of potential therapies for ASD.

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