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.