Deciphering the genetic basis of Hirschsprung disease by whole genome sequencing

Abstract

Hirschsprung disease (HSCR) is a congenital disorder characterized by the absence of enteric ganglia along the lower intestinal tract. The disease is caused by the failure in migration, differentiation and/or proliferation of the enteric neural crest cells to the hindgut, leading to colonic aganglionosis. The differential contributions of rare versus common variants as well as coding versus noncoding variants tend to vary in accordance with the length of aganglionosis. Short-segment HSCR (S-HSCR), accounting for ~80% of the patients, is believed to be genetically complex whereas the rarer subtype, long-segment HSCR (L-HSCR), could be attributed to damaging de novo or recessive mutation. To understand comprehensively the genetic basis across the disease spectrum, we carried out an integrative analysis by high coverage whole-genome sequencing (30-45X) of 443 Chinese S-HSCR, 11 L-HSCR of 10 families (9 trios and 1 quartet) and 493 controls of East Asian ethnicity, aiming to identify novel HSCR genes. Gene-based association analysis on rare variants of S-HSCR not only vindicated the causal roles of the two known genes—RET (SKAT-O P=6.8x10-6) and EDNRB (CMC P=0.0055)—but also revealed higher burden of rare protein-altering variants in PTGS2 and BACE2 (P<0.001) in S-HSCR.