Congenital heart disease and aortic arch variants associated with mutation in PHOX2B. (December 2018)

• Record Type: Journal Article
• Authors: Lombardo, Rachel; Porollo, Aleksey; Cnota, James; Hopkin, Robert
• Is Part Of: Genetics in medicine. Volume 20:Number 12(2018)
• Page Start: 1538
• Page End: 1543
• Publication Date: 2018-12
• Subjects: aortic arch -- cardiac neural crest cell -- congenital central hypoventilation syndrome -- congenital heart disease -- PHOX2B; Medical genetics -- Periodicals; Genetic disorders -- Periodicals; 616.04205
• DOI: 10.1038/gim.2018.34
• Languages: English
• ISSNs: 1098-3600

Abstract

Abstract Purpose Congenital central hypoventilation syndrome (CCHS, OMIM 209880) is a rare autosomal dominant disorder caused by mutation inPHOX2B 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 inPHOX2B in patients with CCHS. Methods A retrospective review of patients with CCHS in conjunction with functional analysis ofPHOX2B 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 inPHOX2B . Results are highly suggestive that alteration or elimination of the homeobox domain conveys significant risk for associated CHD or aortic arch variation.