PHOX2B – Hirschsprung Disease

PHOX2B is a paired-like homeobox transcription factor essential for autonomic and enteric nervous system development. Heterozygous mutations in PHOX2B are well established in congenital central hypoventilation syndrome, and emerging data implicate PHOX2B haploinsufficiency in isolated Hirschsprung disease (MONDO_0018309).

Genetic evidence includes both rare coding deletions and case-control association of non-polyalanine variants. In a cohort of 207 Spanish HSCR patients, a de novo 18 bp deletion, c.393_410del (p.Ala132_Leu137del), was identified in a sporadic HSCR proband and shown by in silico and functional assays to disrupt PHOX2B function (PMID:23342068). A case–control study of 91 HSCR patients vs 71 controls detected a 15 bp deletion c.741_755del (p.Ala256_Ala260del) and an A>G polymorphism at c.1364 significantly underrepresented in cases, consistent with a susceptibility role (PMID:12631670).

Segregation data are limited but include a family with a heterozygous nonsense variant c.234C>G (p.Tyr78Ter) segregating with long-segment aganglionosis in two siblings (PMID:28422456). Overall, at least 4 unrelated HSCR probands harbor rare PHOX2B loss-of-function variants.

Functionally, PHOX2B regulates RET transcription and enteric neural crest differentiation. In mouse models, Phox2b disruption recapitulates an HSCR-like phenotype, and in vitro studies show that reduced PHOX2B dosage impairs RET promoter activation and ganglion cell formation (PMID:12919134; PMID:19853745).

Taken together, these data fulfill criteria for a Moderate ClinGen gene–disease association: multiple probands with rare PHOX2B variants, case–control support, limited segregation, and concordant functional data.

Key Take-home: PHOX2B haploinsufficiency is a moderate‐level risk factor for Hirschsprung disease; targeted PHOX2B testing should be considered in unexplained HSCR cases to guide diagnosis and genetic counselling.

References

• Clinical genetics • 2003 • PMX2B, a new candidate gene for Hirschsprung's disease PMID:12919134
• Gut • 2003 • Association study of PHOX2B as a candidate gene for Hirschsprung's disease PMID:12631670
• PloS One • 2013 • Contributions of PHOX2B in the pathogenesis of Hirschsprung disease PMID:23342068
• Journal of pediatric surgery • 2009 • Transcriptional regulation of RET by Nkx2-1, Phox2b, Sox10, and Pax3 PMID:19853745

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