SU15 - Integrated whole exome sequencing and homozygosity mapping identifies variants in known and novel autism genes involved in neuronal migration and adhesion pathways

Background Genetic heterogeneity of autism makes it challenging to identify the causal genes responsible for its pathogenesis. Although many genes are reported to be associated with autism, recent studies report only a handful of high confidence genes for autism. No disease gene saturation level is attained. There is a need to identify damaging genomic variants which predispose an individual towards autism manifestation. Methods Whole Exome Sequencing (WES) is a reliable technique to identify DNA variants in the coding region of the genome. Based on stringent inclusion-exclusion criteria, the study recruited 50 autism subjects of Indian origin, of which 13 were used for WES. PCR based Fragile X screening was performed to avoid the subjects with autism features. Results Several damaging stop gain/loss mutations encompassing autism genes CDH5, DDX23, CLDN5, and DPP3) were identified with protein truncations ranging from 20�70. These loss of function mutations disrupted important protein domains involved in various autism related pathways such as neuronal migration, synaptic pruning, synaptogenesis, and neuronal adhesion. Homozygosity mapping analysis to identify risk homozygous haplotypes in probands showed evidence of recessive polymorphisms in GIGYF1, SERPINE1, and EPHB6. These recessive alleles were identified across all the samples while polymorphisms in FOLH1, BCKDK, CDH11, and CTCF were specific to few samples. Mutations in language-specific genes, GCFC1 and MRPL19 were found associated with delayed speech language phenotype of autism. Several autism candidate genes WBP11, JMJD6, RBM8A, TRMT2A were identified. Discussion A novel autism candidate gene CLDN5 that physically interacts with genes involved in various autism pathways was identified contributing to the phenotype. CLDN5 was found belonging to the leukocyte transendothelial migration pathway and elevated in autism cortex, impairing the blood brain barrier leading to compensatory gene expression and protein accumulation. This on-going study identified several mutations specific for autism in Indian population, adding to the growing body of mutational spectrum. The implications of these findings will be presented and discussed