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.

A Novel Method for Identifying the Transition Zone in Long-Segment Hirschsprung Disease: Investigating the Muscle Unit to Ganglion Ratio

“…This could be due to clinicopathological differences between the two phenotypes. Variation in genetic profiles have been noted, with mutations in SEMA3C , important for axonal guidance and neural crest cell migration, being more common in long-segment compared to short-segment disease [ 9 , 41 , 42 , 43 ]. In contrast to short-segment disease, submucosal nerve hypertrophy may be limited or absent in rectal biopsies of long-segment HSCR, contributing to longer time to diagnosis of 11–14 days compared to 2–3 days for short-segment disease [ 8 , 9 , 23 ].…”

Association between IKBKAP polymorphisms and Hirschsprung’s disease susceptibility in Chinese children

“…Therefore, it is essential to study the pathogenesis of HSCR, which can better diagnose and treat HSCR patients. So far, a series of genes have been revealed to contribute to the etiology of HSCR, including RET, GDNF, EDNRB, EDN3, ECE1, SOX10, ZEB2, PHOX2B (19)(20)(21)(22)(23)(24)(25). However, there is still much work to unravel the mysteries in the etiology of HSCR.…”

Genetic Background Influences Severity of Colonic Aganglionosis and Response to GDNF Enemas in the Holstein Mouse Model of Hirschsprung Disease

“…HSCR is a complex genetic condition characterized by non-Mendelian inheritance [ 1 , 6 , 7 ], as best exemplified by variation in disease penetrance and severity between family members carrying a similar set of mutations [ 8 , 9 , 10 ]. Current knowledge suggests that most cases are due to different combinations of rare coding variants, common regulatory variants, and/or copy-number variants in many genes important for proper colonization of the developing gastrointestinal tract by ENS progenitors [ 11 , 12 ]. Dozens of such genes have been identified so far [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ].…”

“…Current knowledge suggests that most cases are due to different combinations of rare coding variants, common regulatory variants, and/or copy-number variants in many genes important for proper colonization of the developing gastrointestinal tract by ENS progenitors [ 11 , 12 ]. Dozens of such genes have been identified so far [ 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 ]. The major HSCR-associated gene is RET (REarranged during Transfection) [ 20 , 21 ], which codes for a transmembrane tyrosine kinase that is activated by GDNF (Glial cell line-derived Neurotrophic Factor) upon binding to the co-receptor GFRα1 (GDNF family receptor alpha-1).…”

“…The major HSCR-associated gene is RET (REarranged during Transfection) [ 20 , 21 ], which codes for a transmembrane tyrosine kinase that is activated by GDNF (Glial cell line-derived Neurotrophic Factor) upon binding to the co-receptor GFRα1 (GDNF family receptor alpha-1). Other genes that influence HSCR risk include transcription factors ( SOX10, ZFHX1B, PHOX2B ), EDNRB signaling pathway molecules ( EDNRB, EDN3, ECE1 ), cell adhesion proteins ( L1CAM ), guidance molecules ( SEMA3D ), molecules needed for cell-extracellular matrix interactions ( ITGB1 and COL6 ), and diverse additional genes ( BACE2, NRG1, ERBB2, ADAMTS17, ACSS2 ) [ 11 , 12 ]. Male sex and trisomy 21 are other contributing factors, increasing HSCR risk ~4-fold [ 7 ] and ~130-fold [ 22 ], respectively.…”