Hirschsprung disease: genes and variants

Genes linked to Hirschsprung disease

• RET: Proto-oncogene tyrosine-protein kinase receptor Ret

  Its activation by GDNF-family ligands guides development of the enteric nervous system, kidney, and other tissues. Activating variants cause multiple endocrine neoplasia type 2 and can drive cancer, whereas loss-of-function variants are an important cause of Hirschsprung disease.

  16 disease-causing and 247 uncertain variants in RET are linked to Hirschsprung disease.

• EDNRB: Endothelin receptor type B

  0 disease-causing and 13 uncertain variants in EDNRB are linked to Hirschsprung disease.

Weakly linked (only a few uncertain records): SLC22A1 and SOX10.

Where Hirschsprung disease variants cluster

• RET Protein kinase (positions 724–1016): 7 of 16 disease-causing changes, 1.7× more than its size predicts.

Known disease-causing variants in Hirschsprung disease

Which prediction tools work for Hirschsprung disease

How often each tool ranks a disease-causing variant above a harmless one (AUROC × 100).

• CATVariant: 95 out of 100 (learned from overlapping clinical labels, so this is optimistic)
• SIFT: 94 out of 100
• PolyPhen-2: 90 out of 100 (learned from overlapping clinical labels, so this is optimistic)

Same protein, different disease

• Multiple endocrine neoplasia is also caused by RET variants; they fall mostly in different places as the Hirschsprung disease variants (53 disease-causing).
• Familial medullary thyroid carcinoma is also caused by RET variants; they fall mostly in different places as the Hirschsprung disease variants (13 disease-causing).
• MEN2 phenotype: Unclassified is also caused by RET variants; they fall partly in the same places as the Hirschsprung disease variants (5 disease-causing).

Diseases related to Hirschsprung disease

• Multiple endocrine neoplasia, also linked to RET
• Gastrointestinal stromal tumor, also linked to RET
• Pheochromocytoma, also linked to RET
• Ovarian cancer, also linked to RET
• Waardenburg syndrome, also linked to EDNRB
• Pulmonary arterial hypertension, also linked to EDNRB
• Colorectal cancer, also linked to RET
• Non-small cell lung carcinoma, also linked to RET
• Familial medullary thyroid carcinoma, also linked to RET
• Hepatocellular carcinoma, also linked to RET
• Familial hyperparathyroidism or Hypocalciuric hypercalcaemia, also linked to RET
• MEN2 phenotype: Unclassified, also linked to RET

Frequently asked questions

Which genes are linked to Hirschsprung disease?

In CATVariant, Hirschsprung disease is linked to 2 analyzed proteins: RET (Proto-oncogene tyrosine-protein kinase receptor Ret) and EDNRB (Endothelin receptor type B).

How many genetic variants are linked to Hirschsprung disease?

284 variants: 16 are classified as disease-causing (pathogenic or likely pathogenic) in ClinVar and 260 are of uncertain significance or have conflicting reports.

Which uncertain variants in Hirschsprung disease look disease-causing?

None of the uncertain variants currently reaches the likely-pathogenic range on computable evidence alone.

Which variant effect predictor works best for Hirschsprung disease?

Among tools not trained on clinical labels, SIFT separates this disease's known disease-causing variants from harmless ones best (AUROC 0.94, based on 11 disease-causing and 60 harmless variants).

About this data

Variant–disease links come from ClinVar, Open Targets and UniProt, pooled from the latest public CATVariant analysis of each human protein. Evidence scores use the ACMG/AMP Bayesian points scale with computable criteria only (position among known disease variants, rarity in gnomAD, calibrated predictors, deep mutational scanning); there is no family or patient data, so they prioritise variants for expert review and never classify them.

Download every variant as CSV · Browse all diseases · Methods · About the Center