Relevance to Autism

This gene was identified by TADA (transmission and de novo association) analysis of a combined dataset from the Simons Simplex Collection (SSC) and the Autism Sequencing Consortium (ASC) as a gene strongly enriched for variants likely to affect ASD risk with a false discovery rate (FDR) of < 0.1 (Sanders et al., 2015); among the variants identified in this gene was one de novo loss-of-function (LoF) variant. Additional de novo protein-truncating variants and missense variants in the DNMT3A gene were identified in ASD probands from the SPARK cohort (Feliciano et al., 2019) and the Autism Sequencing Consortium (Satterstrom et al., 2020); TADA analysis in both studies identified DNMT3A as a candidate gene with a false discovery rate (FDR) 0.01. A two-stage analysis of rare de novo and inherited coding variants in 42,607 ASD cases, including 35,130 new cases from the SPARK cohort, in Zhou et al., 2022 identified DNMT3A as a gene reaching exome-wide significance (P < 2.5E-06). Heterozygous variants in the DNMT3A gene are responsible for Tatton-Brown-Rahman syndrome (OMIM 615879), an overgrowth intellectual disability syndrome characterized by tall stature, increased head circumference, and distinctive facial appearance (Tatton-Brown et al., 2014). Clinical review of 55 individuals with Tatton-Brown-Rahman syndrome resulting from de novo DNMT3A variants in Tatton-Brown et al., 2018 determined that autism spectrum disorder (ASD) was observed in 20 individuals. De novo gain-of-function missense variants in the DNMT3A gene were observed in three patients presenting with microcephalic dwarfism and developmental delay (Heyn et al., 2018).

Molecular Function

The protein encoded by this gene is required for genome-wide de novo methylation and is essential for the establishment of DNA methylation patterns during development. It plays a role in paternal and maternal imprinting.

External Links

References