Cai Rongqin, Tan Ya, Wang Mingming, Yu Huijun, Wang Jing, Ren Zhuo, Dong Zhe, He Yiwen, Li Zhi, Lin Li, Gu Ying
Department of Obstetrics and Gynecology, Peking University International Hospital, Beijing, 102206, People's Republic of China.
Be Creative Lab (Beijing) Co. Ltd, Beijing, 101111, People's Republic of China.
Pharmgenomics Pers Med. 2023 Mar 8;16:173-181. doi: 10.2147/PGPM.S394120. eCollection 2023.
Congenital heart disease (CHD) is the most common birth defect with strong genetic heterogeneity. To date, about 400 genes have been linked to CHD, including cell signaling molecules, transcription factors, and structural proteins that are important for heart development. Genetic analysis of CHD cases is crucial for clinical management and etiological analysis.
Whole-exome sequencing (WES) was performed to identify the genetic variants in two independent CHD cases with DNA samples from fetuses and their parents, followed by the exclusion of aneuploidy and large copy number variations (CNVs). The WES results were verified by Sanger sequencing.
In family A, a compound heterozygous variation in gene consisting of c.1132dupA (p.I378fs) and c.1171C>T (p.R391C) was identified in the fetus. The two variants were inherited from the father (c.1132dupA) and the mother (c.1171C>T), respectively. In family B, a hemizygous variant : c.861delG (p.G289Afs*119) was identified in the fetus, which was inherited from the heterozygous mother. We further confirmed that these variants : c.1132dupA and : c.861delG were novel.
The findings in our study identified novel variants to the mutation spectrum of CHD and provided reliable evidence for the recurrent risk and reproductive care options to the affected families. Our study also demonstrates that WES has considerable prospects of clinical application in prenatal diagnosis.
先天性心脏病（CHD）是最常见的出生缺陷，具有很强的遗传异质性。迄今为止，约有400个基因与CHD相关，包括对心脏发育至关重要的细胞信号分子、转录因子和结构蛋白。CHD病例的基因分析对于临床管理和病因分析至关重要。
对两例独立的CHD病例进行全外显子组测序（WES），使用来自胎儿及其父母的DNA样本，随后排除非整倍体和大片段拷贝数变异（CNV）。WES结果通过桑格测序进行验证。
在A家族中，在胎儿中鉴定出一个基因的复合杂合变异，由c.1132dupA（p.I378fs）和c.1171C>T（p.R391C）组成。这两个变异分别从父亲（c.1132dupA）和母亲（c.1171C>T）遗传而来。在B家族中，在胎儿中鉴定出一个半合子变异：c.861delG（p.G289Afs*119），其从杂合子母亲遗传而来。我们进一步证实这些变异：c.1132dupA和：c.861delG是新的。
我们研究中的发现为CHD的突变谱鉴定了新的变异，并为受影响家庭的复发风险和生殖护理选择提供了可靠证据。我们的研究还表明WES在产前诊断中具有相当大的临床应用前景。
