Department of Cardiothoracic Surgery, Wuhan Children's Hospital (Wuhan Maternal and Child Healthcare Hospital), Tongji Medical College, Huazhong University of Science & Technology, Wuhan, China.
Graduate School of Peking Union Medical College & Chinese Academy of Medical Sciences, Beijing, China.
Mol Genet Genomic Med. 2022 May;10(5):e1909. doi: 10.1002/mgg3.1909. Epub 2022 Feb 26.
Previous studies of individuals with hereditary or sporadic congenital heart disease (CHD) have provided strong evidence for a genetic basis for CHD. The aim of this study was to identify novel pathogenic genes and variants in a Chinese CHD family.
Three generations of a family with CHD were recruited. We performed whole exome sequencing for the affected individuals and the proband's unaffected aunt to investigate the genetic causes of CHD in this family. Heterozygous variants carried by the proband and her maternal grandmother, but not the proband's aunt, were selected. The frequencies of the variants detected were assessed using public databases, and their influences on protein function were predicted using online prediction software. The candidate variant was further confirmed by Sanger sequencing of other members of the family.
On the basis of the family's pedigree, the mode of inheritance was speculated to be autosomal dominant with incomplete penetrance. We identified a novel heterozygous missense variant in SOX9 in all affected individuals and one asymptomatic family member, suggesting an inheritance pattern with incomplete penetrance. The variant was not found in any public database. In addition, the variant was highly conserved among mammals, and was predicted to be deleterious by online software programs.
We report for the first time a novel heterozygous missense variant in SOX9 (NM_000346:c.931G>T:p.Gly311Cys) in a Chinese CHD family. Our results provide further evidence supporting a causative role for SOX9 variants in CHD.
先前对遗传性或散发性先天性心脏病（CHD）个体的研究为 CHD 的遗传基础提供了强有力的证据。本研究旨在鉴定一个中国 CHD 家系中的新的致病性基因和变异。
招募了一个 CHD 家系的三代人。我们对受影响个体和先证者的无相关阿姨进行了全外显子组测序，以研究该家系中 CHD 的遗传原因。选择了由先证者及其外祖母携带但先证者的阿姨未携带的杂合变异。使用公共数据库评估所检测到的变异的频率，并使用在线预测软件预测其对蛋白质功能的影响。通过对家系其他成员的 Sanger 测序进一步证实了候选变异。
基于家系的系谱，推测遗传方式为不完全外显的常染色体显性遗传。我们在所有受影响个体和一个无症状的家族成员中发现了 SOX9 中的一个新的杂合错义变异，提示存在不完全外显的遗传模式。该变异未在任何公共数据库中发现。此外，该变异在哺乳动物中高度保守，并且在线软件程序预测其为有害变异。
我们首次报道了一个中国 CHD 家系中 SOX9 （NM_000346:c.931G>T:p.Gly311Cys）中的一个新的杂合错义变异。我们的结果进一步支持了 SOX9 变异在 CHD 中的致病作用。
