RET – Hirschsprung Disease

Hirschsprung disease (HSCR) is a congenital neurocristopathy characterised by aganglionic megacolon (HP:0005260) due to failed neural crest cell migration. The RET proto-oncogene encodes a receptor tyrosine kinase essential for enteric nervous system development. Germline RET variants are the major monogenic cause of familial and sporadic HSCR, with both coding and noncoding alleles contributing to disease susceptibility.

Clinical Validity

RET has a definitive gene-disease association with HSCR. Over 100 HSCR probands across diverse populations have carried heterozygous RET mutations, including 80 probands in a screening study of 80 unrelated cases (10% mutation frequency) (PMID:7633441). Multiple kindreds show co-segregation of RET variants with HSCR in at least 7 affected relatives in two large MEN2A–HSCR families (PMID:7716719), and enhancer variants (c.73+9277T>C) further modify risk (PMID:20598273).

Genetic Evidence

Inheritance is autosomal dominant with reduced penetrance. Segregation analysis identified 7 affected relatives across two MEN2A–HSCR kindreds (PMID:7716719). Case series include 80 HSCR probands with 8 distinct mutations (missense, frameshift, splice, enhancer) (PMID:7633441), and a founder missense allele c.341G>A (p.Arg114His) in ∼7% of Chinese patients (PMID:20532249). Variant spectrum comprises >30 missense (notably cysteine codon substitutions), multiple frameshift/truncating alleles, and the common noncoding enhancer variant c.73+9277T>C. Recurrent founder alleles (p.Arg114His) and population-specific enhancer haplotypes have been documented.

Functional Evidence

HSCR-associated RET variants operate via loss-of-function or dominant-negative mechanisms. Kinase-domain mutants abolish RET/PTC2 transforming activity and reduce tyrosine phosphorylation in fibroblast and pheochromocytoma models (PMID:7647787). Extracellular domain mutations impair receptor maturation and cell surface trafficking, correlating severity of transport defect with HSCR length (PMID:8894691). iPSC models with c.180del (p.Glu61ArgfsTer?) recapitulate early enteric differentiation defects. Enhancer variant c.73+9277T>C disrupts SOX10 binding and reduces RET transactivation (PMID:20598273).

Conflicting Evidence

Common RET polymorphisms (e.g., c.2508C>T p.Ser836=) show variable association, with some alleles underrepresented in sporadic HSCR cohorts (PMID:10980580) and no proven pathogenic effect on splicing or binding.

Integration & Clinical Utility

Robust genetic and experimental data confirm RET as the principal HSCR gene. Diagnostic testing of RET coding exons (especially 10, 11 and kinase-domain exons) and the intronic enhancer should be standard for HSCR patients, guiding surveillance for associated endocrine neoplasia. Given reduced penetrance, genetic counselling must address variable expressivity and secondary modifiers. Key take-home: RET mutation screening informs diagnosis, prognosis, and comprehensive management of Hirschsprung disease.

References

• Surgery • 1995 • Mutational analysis of multiple endocrine neoplasia type 2A associated with Hirschsprung's disease. PMID:7716719
• Human molecular genetics • 1995 • Mutation analysis of the RET receptor tyrosine kinase in Hirschsprung disease. PMID:7633441
• Nature genetics • 1995 • Loss of function effect of RET mutations causing Hirschsprung disease. PMID:7647787
• Human molecular genetics • 1996 • Mechanism of ret dysfunction by Hirschsprung mutations affecting its extracellular domain. PMID:8894691
• American journal of human genetics • 2010 • Differential contributions of rare and common, coding and noncoding Ret mutations to multifactorial Hirschsprung disease liability. PMID:20598273
• PLoS One • 2010 • Haplotype analysis reveals a possible founder effect of RET mutation R114H for Hirschsprung's disease in the Chinese population. PMID:20532249

Evidence Based Scoring (AI generated)