Congenital heart disease and aortic arch variants associated with mutation in PHOX2B

Rachel C. Lombardo, Aleksey Porollo, James F. Cnota, Robert J. Hopkin

Research output: Contribution to journalArticlepeer-review

10 Scopus citations


Purpose: Congenital central hypoventilation syndrome (CCHS, OMIM 209880) is a rare autosomal dominant disorder caused by mutation in PHOX2B that manifests as a consequence of abnormal neural crest cell migration during embryogenesis. Unlike other neurocristopathies, however, its impact on the cardiovascular system has not been previously assessed. This study was an effort to characterize the association between congenital heart disease (CHD) and mutations in PHOX2B in patients with CCHS. Methods: A retrospective review of patients with CCHS in conjunction with functional analysis of PHOX2B mutations associated with CHD was performed. To substantiate functional implications of identified variants, we conducted protein structure analyses and in silico mutagenesis were conducted. Results: The prevalence of CHD among patients with CCHS was significantly greater (30%; p < 0.001) than that of the current estimated prevalence of CHD. The majority of patients had anomalies involving the proximal aortic arch and/or proximal coronary arteries. Variants associated with CHD in this cohort appear to disrupt DNA binding of PHOX2B via alteration of its homeobox domain. Conclusion: This is the first report of an association between CHD and mutation in PHOX2B. Results are highly suggestive that alteration or elimination of the homeobox domain conveys significant risk for associated CHD or aortic arch variation.

Original languageEnglish (US)
Pages (from-to)1538-1543
Number of pages6
JournalGenetics in Medicine
Issue number12
StatePublished - Dec 1 2018


  • PHOX2B
  • aortic arch
  • cardiac neural crest cell
  • congenital central hypoventilation syndrome
  • congenital heart disease

ASJC Scopus subject areas

  • Genetics(clinical)


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