PurposeCongenital 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.MethodsA 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.ResultsThe 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.ConclusionThis 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.Genet Med advance online publication, 15 March 2018; doi:10.1038/gim.2018.34.

中文翻译：

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先天性心脏病和主动脉弓变异与 PHOX2B 突变相关。

目的先天性中枢性低通气综合征 (CCHS, OMIM 209880) 是一种罕见的常染色体显性遗传疾病，由 PHOX2B 突变引起，表现为胚胎发育过程中异常神经嵴细胞迁移的结果。然而，与其他神经嵴病不同的是，它对心血管系统的影响以前没有被评估过。本研究旨在描述先天性心脏病 (CHD) 与 CCHS 患者 PHOX2B 突变之间的关联。方法对 CCHS 患者进行回顾性审查，并结合与 CHD 相关的 PHOX2B 突变的功能分析。为了证实已识别变体的功能意义，我们进行了蛋白质结构分析并进行了计算机诱变。结果 CCHS 患者的 CHD 患病率显着高于（30%；p < 0.001）目前估计的 CHD 患病率。大多数患者的异常涉及近端主动脉弓和/或近端冠状动脉。该队列中与 CHD 相关的变异似乎通过改变其同源框结构域来破坏 PHOX2B 的 DNA 结合。结论这是 CHD 与 PHOX2B 突变之间关联的第一份报告。结果高度暗示同源框域的改变或消除会带来相关 CHD 或主动脉弓变异的重大风险。Genet Med 高级在线出版物，2018 年 3 月 15 日；doi:10.1038/gim.2018.34。大多数患者的异常涉及近端主动脉弓和/或近端冠状动脉。该队列中与 CHD 相关的变异似乎通过改变其同源框结构域来破坏 PHOX2B 的 DNA 结合。结论这是 CHD 与 PHOX2B 突变之间关联的第一份报告。结果高度暗示同源框域的改变或消除会带来相关 CHD 或主动脉弓变异的重大风险。Genet Med 高级在线出版物，2018 年 3 月 15 日；doi:10.1038/gim.2018.34。大多数患者的异常涉及近端主动脉弓和/或近端冠状动脉。该队列中与 CHD 相关的变异似乎通过改变其同源框结构域来破坏 PHOX2B 的 DNA 结合。结论这是 CHD 与 PHOX2B 突变之间关联的第一份报告。结果高度暗示同源框域的改变或消除会带来相关 CHD 或主动脉弓变异的重大风险。Genet Med 高级在线出版物，2018 年 3 月 15 日；doi:10.1038/gim.2018.34。结果高度暗示同源框域的改变或消除会带来相关 CHD 或主动脉弓变异的重大风险。Genet Med 高级在线出版物，2018 年 3 月 15 日；doi:10.1038/gim.2018.34。结果高度暗示同源框域的改变或消除会带来相关 CHD 或主动脉弓变异的重大风险。Genet Med 高级在线出版物，2018 年 3 月 15 日；doi:10.1038/gim.2018.34。