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.