Single-nucleotide polymorphism genotyping and whole-exome and whole-genome sequencing studies have been key for the identification of genetic loci and mutations underlying autism spectrum disorder (ASD) susceptibility. Although none of the risk genes identified so far contribute to more than 1 percent of ASD cases, overall the search for ASD treatments can profoundly benefit from the study of rare and syndromic forms of ASDs.

Loss-of-function mutations in SETD5 have been identified as a relatively frequent cause of intellectual disability (ID) and ASD. SETD5 deletion is also seen in patients with 3p25.3 microdeletion syndrome and has been shown to account for many of the clinical features associated with this syndrome¹,². SET-domain-containing proteins interact with chromatin and catalyze histone H3 and H4 methylation of lysine residues. SETD5 is mainly located within the nucleus, making this protein a strong candidate for regulating histone methylation to control chromatin condensation and consequently gene transcription.

Gaia Novarino plans to employ a SETD5 conditional knockout mouse to identify pathophysiological mechanisms underlying ASD and ID phenotypes. Because SETD5 is expressed in the brain over the course of the entire life, Novarino’s group will also assess the temporal development of ASD-related phenotypes in these mice and determine the potential for rescuing behavioral phenotypes in adulthood. Results from this study will help to further our understanding of neuropathological mechanisms underlying ASD and may point the way toward therapeutic strategies for individuals with SETD5-dependent ASD and ID.