Poster #38: Nathan Zhao

Identification of Candidate Genes with Rare Coding Variants in Tourette Syndrome Patients Using Whole-Exome Sequencing

Nathan Zhao¹; Lionel Sequeira, B.S.¹˒²; Tourette International Collaborative Genetics (TIC Genetics) Group; Jay A. Tischfield, Ph.D.¹˒²; Gary A. Heiman, Ph.D.¹˒²; Jinchuan Xing, Ph.D.¹˒². ¹ Department of Genetics, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA; ² Human Genetics Institute of New Jersey, Rutgers, The State University of New Jersey, Piscataway, NJ 08854, USA

Tourette syndrome (TS) is a heterogeneous neurodevelopmental disorder with a strong genetic component. However, the specific rare variants that contribute to TS susceptibility are not fully understood. Through whole-exome sequencing, many potentially relevant coding variants can be identified, but a high number of variants, along with multiallelic sites, differences in population frequency, and variant quality complicate this process. Here, we analyzed whole-exome sequencing data from singleton TS samples to characterize and reduce this variation. ANNOVAR was used to functionally annotate variants, supplemented by current gnomAD API queries. At multiallelic sites, sample genotypes were matched to their specific alternate allele and corresponding annotation. Filters were applied for VCF quality, rarity in gnomAD populations (allele frequency <0.001), cohort allele frequency (≤0.015), and gnomAD quality/region flags. The analysis of 153 singleton samples identified 974 unique loss-of-function variants across 836 genes after allele-aware population-frequency and quality filtering. These included frameshift deletions, frameshift insertions, stop-gain, and splicing variants, with a median of seven loss-of-function variants per sample. Additional filtering on the brain-expression of the candidate genes further reduced the number of candidate genes. Several genes within this set are of particular interest and are currently being investigated for their potential contribution to Tourette syndrome.