Relevance to Autism

De novo missense variants in the BRAF gene have been identified in ASD probands from the Autism Sequencing Consortium (De Rubeis et al., 2014) and the SPARK cohort (Wang et al., 2020). Single-molecular molecular inversion probe (smMIP) sequencing of 125 genes in over 16,000 cases with neurodevelopmental disorders and comparison of the mutation burden to non-psychiatric controls from ExAC in Wang et al., 2020 identified BRAF as a gene showing a significant burden of ultra-rare (MAF < 0.01%) missense variants with CADD scores equal to or greater than 30 (Mis30 variants) with a false discovery rate (FDR) less than 5%; a total of 11 Mis30 variants in BRAF from 14 individuals were used in this analysis, with 5 of these individuals coming from cohorts with a primary diagnosis of ASD. Patients with cardiofaciocutaneous syndrome mediated by BRAF mutations were found in two reports to frequently exhibit autistic features, such as social impairment and internalizing/externalizing problems, as measured by commonly used ASD-related diagnostic tools (Alfieri et al., 2014; Adviento et al., 2014).

Molecular Function

This gene encodes a protein belonging to the raf/mil family of serine/threonine protein kinases. This protein plays a role in regulating the MAP kinase/ERKs signaling pathway, which affects cell division, differentiation, and secretion. Mutations in this gene are associated with cardiofaciocutaneous syndrome (CFC) [MIM:115150], a disease characterized by heart defects, mental retardation and a distinctive facial appearance. Mutations in this gene have also been associated with various cancers, including non-Hodgkin lymphoma, colorectal cancer, malignant melanoma, thyroid carcinoma, non-small cell lung carcinoma, and adenocarcinoma of lung.

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References