Whole genome sequencing implicates rare variants in sporadic Hirschsprung disease

Abstract

Sporadic Hirschsprung disease (HSCR), representing ~80% of the HSCR cases, is the most common form of the disorder and is believed to be genetically complex. Thus far, studies of rare mutations have discovered more than 10 genes (e.g. RET, EDNRB and GDNF) associated with the disease. The major HSCR gene, RET, have both rare coding mutations and common regulatory variants contributing to the disease. The differential contributions of these rare and common, coding and noncoding variants tend to vary with length of aganglionosis. In view of this, we performed a high coverage whole genome sequencing (~30X) of 11 trios of sporadic patients with the rarer subtype (long segment HSCR; L-HSCR), aiming to identify rare de novo, recessive and compound heterozygous mutations causal to HSCR. Our data show that the combined contribution of the de novo and inherited, both coding and non-coding, variants contribute to the development of ENS and thereby to HSCR. The discovery might shed light on pathways relevant to the etiology of HSCR. This work has been supported by HMRF grant 01121516 to MMGB.