Evaluation of candidate genes for Hirschsprung disease using targeted sequencing

Abstract

Hirschsprung Disease (HSCR), or congenital aganglionic megacolon, is a relatively rare and complex genetic disorder characterised by the congenital absence of enteric neurons along a variable length of the distal intestine. Patients present with bowel obstruction and the disease may be fatal unless treated surgically. There is significant population variation in the incidence of the disease, and its incidence in Chinese is one of the highest in the world (1.4/5,000 live-births). Through the International Hirschsprung Disease Consortium exome sequencing project, candidate genes recurrently mutated with either de novo and/or inherited damaging variants were identified. In this follow-up study, we investigate if these genes are definitive genetic risk factors for HSCR in a larger number of patients. We screened 12 newly identified genes for mutations in 1200 Chinese and Caucasian HSCR patients, performed target sequencing using xGen®Lockdown® Custom Probes for enrichment of the sequences of the selected genes and high-throughput sequencing with depth 700X. Latest findings of this study will be presented to provide insights on whether the mutated genes identified through our exome study really involved in the pathogenesis of HSCR. This project is supported by the HMRF grant 02131866 to MMGB.