Rare variants in sporadic Hirschsprung disease patients

Abstract

Sporadic Hirschsprung disease (HSCR), accounting for ~80% of the patients, represents the most common form of the disorder and is believed to be genetically complex. Studies of rare mutations have discovered more than 10 genes associated with HSCR. The major HSCR-susceptibility gene, RET, have both rare coding sequence mutations and common regulatory variants contributing to the disease. The differential contributions of rare and common, coding and noncoding variants tend to vary in accordance with gender and length of aganglionosis. In view of this, we performed a whole genome sequencing study of 5 trios of sporadic patients with the rarer subtype (long segment HSCR) to identify rare mutations causal to HSCR. Our data show that de novo as well as inherited variants contribute to the development of ENS and thereby to HSCR. The discovery might give rise to a new insight into the disease pathophysiology.