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This summary details the association of KIF26A with Hirschsprung disease. Two independent studies have implicated KIF26A in a syndrome characterized by severe megacolon that resembles Hirschsprung disease, suggesting that variants in this gene disrupt normal enteric nervous system development. The narrative is supported by both clinical segregation data and functional studies that elucidate the underlying disease mechanism. This association is highly relevant for diagnostic decision‑making and can guide genetic screening for patients presenting with enteric dysmotility symptoms.
Clinically, two families have been reported in which affected individuals harbor homozygous truncating variants in KIF26A, consistent with an autosomal recessive inheritance pattern (PMID:36564622). In these families, the variant segregated with a severe phenotype manifesting as megacolon and other gastrointestinal abnormalities. Detailed pedigree analyses revealed that the identified variants co‐segregated with the disease, reinforcing their pathogenic role. The clinical findings align with the phenotype observed in Hirschsprung disease, thereby strengthening the gene‑disease relationship.
Genetic evidence further supports the association. One representative variant, c.3440dup (p.Ala1148fs), was identified in affected individuals and is predicted to result in a frameshift leading to a premature truncation of the protein. This variant meets established criteria for pathogenicity based on its loss‑of‑function effect. The variant, along with similar truncating changes reported in the literature, provides a consistent genetic basis for the disorder. Such findings underscore the molecular etiology of the condition and support the use of genetic testing in clinical practice.
In terms of inheritance and segregation, the disorder follows an autosomal recessive pattern. The homozygous nature of truncating variants in affected individuals from the reported families supports this mode of inheritance. Although the exact number of additional affected relatives was not detailed, the segregation analysis in these two families offers compelling evidence for a causal relationship (PMID:36564622). Robust co‐segregation with the clinical phenotype in these families provides further validation of this genetic mechanism.
Functional studies provide key experimental evidence for KIF26A’s role in the disease. In murine models and human iPSC‑derived organoids, loss‑of‑function of KIF26A resulted in defects in radial migration, axonal growth, and increased apoptosis. These functional disruptions were shown to impact critical signaling pathways, including those related to GDNF‑Ret, which are essential for proper enteric nervous system development (PMID:36228617). Rescue experiments in these models further confirmed that the loss of KIF26A function directly contributes to the observed cellular and developmental abnormalities. This experimental data robustly corroborates the clinical findings.
Integrating the clinical, genetic, and functional evidence provides a coherent picture of the disease etiology. Two independent families harboring homozygous truncating variants in KIF26A, combined with strong experimental validation, firmly establish a strong association with Hirschsprung disease. Although additional supporting evidence exists, the collected data meet the criteria for a robust gene‑disease relationship according to ClinGen standards. The convergence of these multiple lines of evidence makes KIF26A a critical target for diagnostic genetic screening.
Key Take‑home: The strong association between KIF26A loss‑of‑function and Hirschsprung disease supports its use as a valuable diagnostic marker and provides a basis for the development of targeted therapeutic strategies.
Gene–Disease AssociationStrongTwo independent families with homozygous truncating variants segregating with Hirschsprung disease phenotype (PMID:36564622) and supported by robust functional data (PMID:36228617). Genetic EvidenceStrongHomozygous truncating variant c.3440dup (p.Ala1148fs) identified in affected individuals in 2 families is consistent with autosomal recessive inheritance and a loss‑of‑function mechanism. Functional EvidenceStrongAnimal models and in vitro studies demonstrate that loss of KIF26A function leads to disrupted neuronal migration and signaling pathways, recapitulating key features of the disease (PMID:36228617). |