Paediatric pseudo-obstruction syndrome

Gene: RET

Green List (high evidence)

Biallelic cases:
PMID: 34267336 Arteche-López et al., 2021
Male proband, diagnosed with Hirschsprung disease at birth, severe enterocolitis and abdominal sepsis resulted in complete colonic removal. Similarly affected brother. Both sibs were homozygous for RET c.1711G>A p.(Asp571Asn) variant. Asymptomatic parents were het carriers. 7 hets in gnomAD v4, no homozygotes. Conflicting classification in ClinVar (VUS/LB).

PMID: 9090527 Seri et al., 1997
Homozygous RET c.938G>A, p.R313Q mutation identified in a child born of consanguineous parents is associated with the most severe Hirschsprung phenotype (total colonic aganglionosis with small bowel involvement). Healthy first-cousin parents were heterozygous for the variant. 45 heterozygotes reported in gnomAD v4 with this variant; no homozygotes. VUS in ClinVar.

Created: 20 May 2026, 1:03 p.m. | Last Modified: 20 May 2026, 1:03 p.m.

Panel Version: 2.6

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, NOT imprinted

Phenotypes
{Hirschsprung disease, susceptibility to, 1}, OMIM:142623

Publications

• 9090527
• 34267336

Green List (high evidence)

The rating of this gene has been updated to Green and the mode of inheritance set to 'MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown' following NHS Genomic Medicine Service approval.

Created: 1 Feb 2023, 7:44 a.m. | Last Modified: 1 Feb 2023, 7:44 a.m.

Panel Version: 0.216

Comment on list classification: This gene should be rated GREEN as this gene was associated with susceptibility to Hirschsprung disease from multiple unrelated cases and supported by functional studies from animal models.

A meta-analysis of genetic studies conducted from 1970 to 2013 on patients with Hirschsprung disease identified 21 positive genetic studies, out of which 17 cases involved RET gene. These included 11 variants.

In addition, the introduction of a missense mutation in RET gene (S811F) in mice resulted in intestinal aganglionosis (incidence: 50%) or hypoganglionosis (50%), impaired differentiation of enteric neurons, defecation deficits, and increased lethality. This demonstrates that a single RET missense mutation alone induces intestinal aganglionosis via a dominant-negative mechanism (PMID:36521661).

This gene has already been associated with Hirschsprung disease in OMIM.

Created: 30 Dec 2022, 6:29 p.m. | Last Modified: 30 Dec 2022, 6:29 p.m.

Panel Version: 0.121

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
{Hirschsprung disease, susceptibility to, 1}, 142623; {Hirschsprung disease, protection against}, 142623

Publications

• 21960833
• 31848803
• 34092334
• 36521661

Review submitted on behalf of Dr. Anna Rybak and Dr. Osvaldo Borreli, Great Ormond Street Hospital for Children NHS Foundation Trust. Gene group: Genes involved in Hirschsprung disease (HSCR) in humans and models of megacolon. Protein function: Expressed in the neural crest cells of the enteric ganglia and encodes a member of the receptor tyrosine kinase family of transmembrane receptors.

Created: 20 Dec 2022, 3:32 p.m. | Last Modified: 20 Dec 2022, 3:32 p.m.

Panel Version: 0.2

Mode of inheritance
MONOALLELIC, autosomal or pseudoautosomal, imprinted status unknown

Phenotypes
Gain in function mutation associated with intestinal ganglioneuromas leading to increased cell number in the myenteric plexus and dysmotility

Publications

• 31848803