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Hirschsprung disease is characterized by congenital aganglionosis of the distal bowel leading to functional obstruction. ERBB3, a member of the epidermal growth factor receptor family, has emerged as a novel causative gene through its critical role in enteric neural crest progenitor development. In a cohort of 8 unrelated patients presenting with Hirschsprung disease and chronic intestinal pseudo-obstruction, biallelic ERBB3 variants were identified by trio-exome sequencing under an autosomal recessive model ([PMID:33497358]).
Genetic analyses revealed compound heterozygous and homozygous ERBB3 alleles, including missense and loss-of-function changes segregating with disease in multiple families. A representative variant is c.2695G>A (p.Val899Met), which affects the kinase-docking interface and was absent from population databases ([PMID:33497358]). No additional affected relatives beyond probands were reported, consistent with recessive inheritance.
Patient-derived fibroblast RT-qPCR and Neuro-2a cell immunoblot assays demonstrated that these ERBB3 variants lead to reduced receptor expression or impaired phosphorylation upon heregulin stimulation, confirming loss of function ([PMID:33497358]). Complementary work in a conditional Erbb3 knockout mouse revealed disrupted enteric progenitor survival and differentiation, recapitulating the aganglionic phenotype seen in humans.
No studies to date have refuted the association, and there is concordance between human genetic findings and animal models. Overall, the evidence supports a Moderate clinical validity for ERBB3 in Hirschsprung disease based on multiple probands, functional assays, and a relevant mouse model.
Key Take-home: ERBB3 should be included in genetic testing panels for autosomal recessive Hirschsprung disease, as biallelic loss-of-function variants reliably predict enteric nervous system failure.
Gene–Disease AssociationModerate8 probands with biallelic ERBB3 variants in multiple families, consistent recessive segregation, and functional concordance in mouse model Genetic EvidenceModerate8 probands with compound heterozygous or homozygous LOF and missense ERBB3 variants (c.2359A>C, c.2695G>A, c.3297del) demonstrating autosomal recessive inheritance ([PMID:33497358]) Functional EvidenceModerateConditional Erbb3-deficient mouse model recapitulates enteric nervous system defects and patient-derived cell assays show impaired receptor phosphorylation ([PMID:33497358]) |