Relevance to Autism

Heterozygous variants in the STXBP1 gene are responsible for a form of early-onset epileptic encephalopathy (EIEE4; OMIM 612164) highlighted by epilepsy and often severe intellectual disability (Saitsu et al., 2008; Deprez et al., 2010). ASD has been observed in individuals with STXBP1 variants both in the presence and absence of epilepsy and/or intellectual disability (Campbell et al., 2012; Neale et al., 2012; Deciphering Developmental Disorders Study, 2015; Yuen et al., 2015; Wang et al., 2016). A systemic review of 147 patients with STXBP1 encephalopathy, including 45 previously unreported patients, demonstrated that autism or autistic features were observed in approximately 20% of published cases, although the actual number of cases with autism/autistic features may be greater due to the focus of most studies on the intellectual disability/epilepsy phenotype (Stamberger et al., 2016). Variants in STXBP1 have also been identified in patients presenting with atypical Rett syndrome, with affected individuals frequently exhibiting autistic features and stereotyped movements (Romaniello et al., 2015; Olson et al., 2015). A de novo missense variant that was predicted to be deleterious (defined as having an MPC score 2) was identified in an ASD proband from the Autism Sequencing Consortium in Satterstrom et al., 2020; subsequent TADA analysis of de novo variants from the Simons Simplex Collection and the Autism Sequencing Consortium and protein-truncating variants from iPSYCH in this report identified STXBP1 as a candidate gene with a false discovery rate (FDR) between 0.01 and 0.05 (0.01 < FDR 0.05). An additional de novo loss-of-function variant and a potentially damaging missense variant in the STXBP1 gene were identified in ASD probands from the SPARK cohort in Zhou et al., 2022; 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 this report identified STXBP1 as a gene reaching exome-wide significance (P < 2.5E-06).

Molecular Function

This gene encodes a syntaxin-binding protein. The encoded protein appears to play a role in release of neurotransmitters via regulation of syntaxin, a transmembrane attachment protein receptor. Mutations in this gene have been associated with infantile epileptic encephalopathy-4.

External Links

References