Computational identification of Hirschsprung disease susceptibility genes

Hirschsprung disease (HSCR), or congenital intestinal aganglionosis, is a male-biased, rare developmental
defect with multifactorial inheritance, high heritability, syndromic associations, and genetic heterogeneity.
More than 24 genes and 9 loci underlie HSCR pathogenesis and explain 62% of its population attributable risk
(PAR). Molecular diversity is extensive in HSCR with coding and regulatory, rare and common, single
nucleotide, insertion/deletion and copy number variants, from segregating pathogenic alleles or de novo
mutations (DNMs). Despite this heterogeneity 53% of HSCR variants disrupt signaling of two key proteins,
RET and/or EDNRB, which along with 11 genes comprising a gene regulatory network controlling RET and
EDNRB gene expression in the developing enteric nervous system. We have just completed whole genome
sequencing of 766 unrelated HSCR cases, their 99 affected and 1,293 unaffected first-degree relatives. Here we
propose state-of-the-art data analyses to enable a near complete genetic characterization of HSCR by improved
detection of all variant types in coding and cis regulatory elements (CREs). In addition, using other available
genetic data, we test whether HSCR genes contribute to the risk of associated neurocristopathies, to explain the
wide spectrum of HSCR phenotypes.

Grant Number: 1R03HD116004-01
NIH Institute/Center: NIH
Principal Investigator: Sumantra Chatterjee