RET – Hirschsprung disease, susceptibility to 1

RET is a well‐established autosomal dominant gene associated with Hirschsprung disease susceptibility type 1 (HSCR1). Clinical validity is classified as Definitive based on over 100 unrelated probands, segregation in multiple independent families, and concordant experimental data demonstrating loss‐of‐function effects on enteric neural crest development. Genetic studies span familial linkage and case–control cohorts, confirming RET as the major monogenic contributor to HSCR1.

Inheritance is autosomal dominant with incomplete penetrance. Segregation analyses in three kindreds and one multigenerational family demonstrate co‐segregation of RET coding variants with HSCR (e.g., 6 probands with extracellular missense and nonsense variants) (PMID:8114939). Case series identified 8 RET mutations in 80 HSCR probands (PMID:7633441) and a novel co‐segregating p.Ser922Tyr variant in 5 affected individuals in a single kindred (PMID:28799054). Large cohort screening of 601 Chinese patients revealed RET variants in 100 individuals, including missense, nonsense, frameshift, splice and in‐frame deletions, particularly clustering in the extracellular domain (PMID:22174939).

The RET variant spectrum includes over 60 distinct missense and loss‐of‐function alleles (nonsense, frameshift, splice) and one in‐frame deletion (c.988C>T (p.Arg330Trp)). A common intronic enhancer variant (rs2435357T) acts as a low‐penetrance modifier. No strong founder alleles have been reported, reflecting broad allelic heterogeneity across populations.

Mechanistically, HSCR‐associated RET mutations generally result in loss of receptor function by impairing protein maturation, membrane localization, or kinase activity. Extracellular domain mutants often block glycosylation and trafficking, while kinase domain mutations abolish autophosphorylation, acting in a dominant‐negative manner to disrupt downstream GDNF‐RET signaling essential for enteric neural crest migration.

Functional assays in cell lines and animal models support pathogenicity. In COS‐7 and NIH3T3 cells, RET kinase–domain mutations abrogate phosphorylation and transforming activity (PMID:7647787), while zebrafish morpholino knockdown of RET ligands and mutant RET expression reduce enteric neuron counts, phenocopying human aganglionosis (PMID:29601828).

Common and rare RET variants interact with modifier loci (e.g., NRG1) to influence penetrance and aganglionosis length, underscoring the complex, multifactorial etiology of HSCR1.

Genetic and functional evidence collectively support definitive clinical validity for RET in HSCR1. RET variant testing informs diagnosis, familial risk assessment, and genetic counseling in Hirschsprung disease.

References

• Nature • 1994 • Mutations of the RET proto-oncogene in Hirschsprung's disease. PMID:8114939
• Human molecular genetics • 1995 • Mutation analysis of the RET receptor tyrosine kinase in Hirschsprung disease. PMID:7633441
• Pediatric surgery international • 2017 • Identification of a novel variant of the RET proto-oncogene in a novel family with Hirschsprung's disease. PMID:28799054
• PLoS One • 2011 • RET mutational spectrum in Hirschsprung disease: evaluation of 601 Chinese patients. PMID:22174939
• Nature Genetics • 1995 • Loss of function effect of RET mutations causing Hirschsprung disease. PMID:7647787
• Gastroenterology • 2018 • Identification of Variants in RET and IHH Pathway Members in a Large Family With History of Hirschsprung Disease. PMID:29601828

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