22256
Increased Frequency of TSC2 Missense Mutations in Non-Syndromic Autism
Friday, May 13, 2016: 11:30 AM-1:30 PM
Hall A (Baltimore Convention Center)
L. Kalsner1, B. Manwani2, J. Twachtman-Bassett3, E. Cornell4, L. Derynioski5, A. Milanese6, T. Dumont-Mathieu7, C. Stanley8 and S. Chamberlain9, (1)Connecticut Children's Medical Center, Hartford, CT, (2)Neurology, University of Connecticut Health Center, Farmington, CT, (3)Connecticut Children's Medical Center, Colchester, CT, (4)Research, Connecticut Children's Medical Center, East Hartford, CT, (5)Neurology, Connecticut Children's Medical Center, Farmington, CT, (6)Divison of Developmental and Rehabilitation Medicine, Department of Pediatrics, Connecticut Children's Medical Center, Farmington, CT, (7)Division of Developmental and Rehabilitation Medicine, Department of Pediatrics, Connecticut Children's Medical Center, Farmington, CT, (8)Courtagen Life Sciences Inc, woburn, MA, (9)Genetics and Genome Sciences, University of Connecticut Health Center, Farmington, CT
Background: Tuberous sclerosis complex (TSC) is a neurogenetic disorder caused by heterozygous loss-of-function mutations in either the TSC1 or TSC2 genes. Classically the condition is diagnosed based on a constellation of clinical findings including hypomelanotic macules, angiofibromas, retinal hamartomas, cortical dysplasias, subependymal nodules, cardiac rhabdomyomas, and renal angiomyolipomas. It is also recognized that autism spectrum disorder is common in children with TSC, affecting roughly 50% of patients. TSC genes operate by inhibiting the mammalian target of rapamycin complex 1 (mTORC1), a complex pathway that controls translation and cell growth. Autism spectrum disorder (ASD) is neurodevelopmental disorder, characterized by impairments in social interaction, social communication and restricted or repetitive patterns of behavior. Numerous genes have been identified in which mutations cause or contribute to autism risk. Though mutations in TSC2 are known to cause tuberous sclerosis complex which is commonly associated with autism, mutations have not been known to independently increase risk for autism in the absence of clinical manifestations of TSC. We hypothesized that missense mutations in the TSC2 gene may contribute to risk for ASD, in the absence of classic signs of tuberous sclerosis complex.
Objectives: The objective of this study was to compare the frequency of TSC2 missense mutations in children with autism spectrum disorder to that found in the general population.
Methods: Peripheral blood samples were collected from 50 children diagnosed with non-syndromic autism at the Connecticut Children’s Medical Center (CCMC) in the autism spectrum assessment program (ASAP) after obtaining consent according to protocols approved by the Institutional Review Board at CCMC. TSC2 sequencing was performed by Courtagen Diagnostics Laboratory as part of a multi gene panel using the Illumina MiSeq sequencing system. Variants identified were compared with reported variants in the Exome Aggregation Consortium (ExAC) database, using chi-square test.
Results: In our patient population, 8 out of 50 patients (16%) with non-syndromic autism were found to have non-synonymous missense mutations in the TSC2 gene. This is significantly higher than the reported prevalence of 1.3% in the general population, with 766 missense and loss-of-function TSC2 variants found in approximately 60,000 individuals as reported in the ExAC database, p <0.01.
Conclusions: Our study concludes that patients with missense mutations in the TSC2 gene, but no clinical manifestations of tuberous sclerosis complex, may be at higher risk of autism. This may be due to the disruption of neuronal function through effects on the mTORC1 pathway and may raise the possibility of novel therapeutic targets for treatment of autism in the future.
