The Emerging Genetic Landscape of Hirschsprung Disease and Its Potential Clinical Applications

Abstract

Hirschsprung disease (HSCR) is the leading cause of neonatal functional intestinal obstruction. It is a rare congenital disease with an incidence of one in 3,500-5,000 live births. HSCR is characterized by the absence of enteric ganglia in the distal colon, plausibly due to genetic defects perturbing the normal migration, proliferation, differentiation, and/or survival of the enteric neural crest cells as well as impaired interaction with the enteric progenitor cell niche. Early linkage analyses in Mendelian and syndromic forms of HSCR uncovered variants with large effects in major HSCR genes including RET, EDNRB, and their interacting partners in the same biological pathways. With the advances in genome-wide genotyping and next-generation sequencing technologies, there has been a remarkable progress in understanding of the genetic basis of HSCR in the past few years, with common and rare variants with small to moderate effects being uncovered. The discovery of new HSCR genes such as neuregulin and BACE2 as well as the deeper understanding of the roles and mechanisms of known HSCR genes provided solid evidence that many HSCR cases are in the form of complex polygenic/oligogenic disorder where rare variants act in the sensitized background of HSCR-associated common variants. This review summarizes the roadmap of genetic discoveries of HSCR from the earlier family-based linkage analyses to the recent population-based genome-wide analyses coupled with functional genomics, and how these discoveries facilitated our understanding of the genetic architecture of this complex disease and provide the foundation of clinical translation for precision and stratified medicine.

Keywords: GWAS; Hirschsprung disease; aganglionosis; common variants; genetic architecture; genetics; next-generating sequencing; rare variants.

Figure 1

Current understanding of the genetic architecture of HSCR. The x-axis denotes the minor allele frequency (MAF) of variants and the y-axis denotes the effect size. HSCR-associated genetic variants range from variants with extremely low MAF and very large effect size (upper-left side of the plot) to the common/low-frequency variants with small to large effect size (right side of the plot). These variants have been reported in the HSCR loci shown in the upper panel and can cause HSCR with a wide spectrum of severity as denoted in the right panel. On one end of the phenotypic spectrum lies the syndromic HSCR and TCA/L-HSCR, which are the rarer and severe form of HSCR whereas on the other end lies the commonest form of HSCR, i.e., sporadic S-HSCR.

Figure 2

Biological pathways implicated in HSCR. Many of the reported HSCR-associated genes converge into several biological pathways as shown in this figure. The schematic diagram illustrates an ENCC migrating through the gut and its interaction with the surrounding environment including the ECM. The ENCC receives cues from the surrounding environment through different signaling molecules that regulate the cellular machinery as well as feedback interaction with the surrounding niche. The potential therapeutic approaches that are currently under investigation are also shown.