ClinGen Dosage Sensitivity Curation Page


  • Curation Status: Complete

Location Information

Select assembly: (NC_000010.10) (NC_000010.11)
Evidence for haploinsufficiency phenotype
PubMed ID Description
11694544 Amiel & Lyonnet 2001 wrote "Hirschsprung disease, associated syndromes, and genetics: a review" describing over 80 variants in RET (including large deletions encompassing the enire gene, microdeletions and insertions, nonsense, missense and splicing mutations identified in individuals with Hirschsprung disease (PMIDs 7633441, 8654369 and 9090527). The authors described haploinsufficiency as the most likely disease mechanism.
11953745 Gabriel et al. 2002 described four probands with RET nonsense or frameshift mutations, and three families harbored sequence alterations that could affect normal RET splicing. They also showed that other probands and families had other heterozygous RET mutations or RET-dependent loci described as RET expression modifiers.
30970187 Tilghman et al. 2019 genotyped and exome-sequenced samples from 190 patients with Hirschsprung's disease to quantify the genetic burden in patients with this condition. At least one identifiable genetic risk factor was found in 72.1% of the patients, and at least 48.4% of patients had a heterozygous structural or regulatory deficiency in the gene encoding RET gene. According to the authors, this finding highlights the fact that reduced RET expression is the predominant cause of Hirschsprung?s disease.

Haploinsufficiency phenotype comments:

Deletions and loss of function mutations are associated with both familial and sporadic Hirschsprung disease. A complete review is available online in Gene Reviews and PMIDs 11694544, 15617541, and 17965226. IMPORTANT: Deletions and loss of function mutations are NOT associated with MEN (Multiple endocrine neoplasia) type 2A, 2B, and Familial Medullary Thyroid Cancer. According to GeneReviews, these other health conditions are associated with RET gain-of-function mutations: (

  • Triplosensitivity score: 0
  • Strength of Evidence (disclaimer): No evidence for dosage pathogenicity