Relevance to Autism

Mutations in TSC2 cause the autosomal dominant disorder tuberous sclerosis (TSC). About 25% of individuals with TSC have autism and 40%-50% meet diagnostic criteria within the autistic spectrum disorders (Smalley et al., 1998). Schaaf et al., 2011 and Kelleher et al., 2012 identified a number of TSC2 missense variants in ASD probands that were not observed in control populations. Rare de novo and inherited missense variants in TSC2 have been identified in ASD probands from the Simons Simplex Collection (ORoak et al., 2012; Bahl et al., 2013; Iossifov et al., 2014), as well as in ASD probands from the Autism Clinical and Genetic Resources in China (ACGC) cohort (Wang et al., 2016). Targeted gene panel screening of a clinical population of 100 children with ASD from the Connecticut Childrens Medical Center Autism Neurogenetics Program in Kalsner et al., 2016 identified 18 rare TSC2 variants in ASD cases (18.0%) compared to 9.8% in the ExAC database (P = 0.0062); the statistical enrichment of rare TSC2 variants in ASD cases remained significant after multiple comparisons correction. Addtional de novo loss-of-function variants and potentially damaging missense variants in the TSC2 gene were reported in ASD probands from the Autism Sequencing Consortium, the MSSNG cohort, and 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 TSC2 as a gene reaching exome-wide significance (P < 2.5E-06).

Molecular Function

The product of this gene is believed to be a tumor suppressor and is able to stimulate specific GTPases.

External Links

References