Exonic de novo mutations in sporadic Hirschsprung disease

Abstract

Hirschsprung disease (HSCR) is a disorder of the enteric nervous system (ENS) and is characterized by the absence of enteric neurons along a variable length of the intestine. HSCR most commonly presents sporadically, although it is familial in 5-20% of the patients. The sporadic form of the disorder is believed to be a genetically complex disease. To assess the role of de novo mutations in sporadic HSCR, we performed exome sequencing on 20 HSCR patients, predominantly females with long segment HSCR and their unaffected parents. We identified and confirmed 24 de novo mutations (18 SNVs, 6 Indels) in 17 different genes (1.2 per trio). Non-synonymous de novo mutations were identified in RET in 8 out of 20 patients, corroborating previous findings that RET is the major genetic contributor in long-segment HSCR. A replication study in independent HSCR patients, gene burden tests and functional analysis in both cell lines and zebra fish are currently being conducted. Interestingly, some of the genes harboring de novo mutations are members of pathways involved in the development of the ENS and the encoded proteins interact with known key signaling molecules. We will present all data which will enable us to make conclusion on whether, de novo mutations in genes other that RET also contribute to the development of sporadic HSCR.