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ATP7A has been implicated as a novel susceptibility gene for Hirschsprung disease (Hirschsprung disease) through integrative genomic and functional analyses. In a complementary study combining whole-exome sequencing of two unrelated HSCR probands and transcriptome profiling of murine embryonic enteric nervous system tissues, rare ATP7A variants were identified in both index cases and in additional HSCR patients, suggesting a contributory role in disease predisposition (2 probands) (PMID:33151932). The lack of clear Mendelian segregation and small number of affected families support a limited genetic evidence base.
Functional knockout of ATP7A in genome-edited neuronal cell clones resulted in impaired neural crest–derived cell differentiation, proliferation, and survival, consistent with the enteric aganglionosis phenotype of HSCR (PMID:33151932). No conflicting reports have challenged this preliminary association.
Key take-home: Rare ATP7A variants may contribute to Hirschsprung disease risk and warrant further study in larger cohorts to clarify their diagnostic and therapeutic utility.
Gene–Disease AssociationLimitedVariants identified in 2 unrelated probands and additional patients with HSCR; preliminary functional support Genetic EvidenceLimitedEvidence from 2 probands without clear segregation; candidate susceptibility variants observed in additional cases Functional EvidenceModerateGenome-edited neuronal cell knockout impaired differentiation and survival consistent with HSCR phenotype |