TSC2 Gene Missense Mutations May be Associated with Non Syndromic Autism (S10.002)

Objective: To investigate the role of TSC2 gene missense mutations in autism spectrum disorder. Background: Tuberous sclerosis complex (TSC) is a neurogenetic disorder caused by heterozygous loss of function mutations in either TSC1 or TSC2 gene. TSC genes operate by inhibiting the mammalian target of rapamycin complex1 (mTORC1), a pathway that controls cell growth. Classically, TSC is diagnosed based on a constellation of clinical findings including hypomelanotic macules, angiofibromas, cortical dysplasia and cardiac rhabdomyomas. It is well recognized that autism spectrum disorder (ASD) is common in children with TSC, affecting roughly 50[percnt] of patients. ASD is a neurodevelopmental disorder, characterized by impairments in reciprocal social communication and stereotyped behaviors. We hypothesized that missense mutations in TSC2 gene may contribute to risk for ASD, in the absence of classic signs of TSC. Methods: Peripheral blood samples were collected from 70 children diagnosed with non-syndromic autism at the Connecticut Children’s Medical Center (CCMC) in the autism assessment program after obtaining consent (protocols approved by IRB at CCMC). TSC2 sequencing was performed by Courtagen Diagnostics Lab as part of a multi gene panel using Illumina MiSeq sequencing system. Variants identified in TSC2 were compared with reported variants in the Exome Aggregation Consortium (ExAC) database using chi-square test. Results: 12 out of 70 patients (17[percnt]) with ASD were found to have non-synonymous missense mutations in TSC2 gene. This is significantly higher than the reported prevalence of 4,395 missense and loss of function TSC2 variants in 54,084 exomes (8.1[percnt]) in theExAC database, p 0.05. Conclusions: Our study concludes that patients with missense mutations in TSC2 gene, but with no clinical manifestations of tuberous sclerosis, may be at higher risk of autism. This may due to disruption of neuronal function through effects on the mTORC1 pathway, and may raise the possibility of novel therapeutic targets for autism treatment. Disclosure: Dr. MANWANI has nothing to disclose. Dr. Chamberlain has nothing to disclose. Dr. Twachtman- Bassett has nothing to disclose. Dr. Cornell has nothing to disclose. Dr. Stanley has received personal compensation for activities with Courtagen Diagnostics. Dr. Kalsner has nothing to disclose.