Poster #66: Subramanian Krishnamurthy

Identifying Candidate Genes for Chronic Tic Disorder from de novo Copy Number Variants

Krishnamurthy, Subramanian1, Koesterich, Justin1, Sequeira, Lionel1, Tourette International Collaborative Genetics (TIC Genetics) group, Tischfield, Jay1, Heiman, Gary1, and Xing, Jinchuan1 Detailed Affiliations: 1Rutgers, the State University of New Jersey, Department of Genetics and the Human Genetics Institute of New Jersey, Piscataway, NJ 08854, USA

Chronic tic disorder (CTD), including Tourette syndrome (TS) and related tic disorders, is a heterogeneous neurodevelopmental condition with onset in childhood that affects approximately 1-3% of the population. The high prevalence of neurodevelopmental and psychiatric comorbidities among affected individuals suggests a shared underlying genetic architecture; however, the contribution of structural variation to CTD risk remains incompletely understood. Here, we systematically characterized de novo copy number variants (CNVs) in simplex trios from the Tourette International Collaborative Genetics (TIC Genetics) study using complementary genomic approaches. Analysis of high-density microarray data from 697 simplex trios identified 44 high-confidence de novo CNVs. To enhance structural variant discovery, we developed a novel analytical framework optimized for low-coverage whole-genome sequencing (3×-8×), which identified 495 de novo CNVs across 171 simplex trios. Integration and functional annotation of genes disrupted by these de novo CNVs highlight a set of candidate risk genes and pathways potentially contributing to CTD pathogenesis. These findings expand the catalog of de novo structural variation in CTD and provide a foundation for elucidating the molecular mechanisms underlying clinical heterogeneity and genetic susceptibility in CTDs. Functional characterization of candidate genes in cellular and mouse models will provide critical insights into the biological mechanisms underlying CTD susceptibility and phenotypic heterogeneity.