产前超声诊断先天性心脏病胎儿的基因特征

目的 观察产前超声诊断先天性心脏病（CHD）胎儿的基因特征。方法 回顾性分析613胎经产前超声诊断CHD的单胎胎儿资料，并将其分为8类心脏结构异常；其中40胎因染色体核型分析和/或染色体微阵列分析（CMA）提示良性拷贝数变异（CNV）或临床意义不明确的CNV（VUS）而接受全外显子测序（WES）。结果 613胎CHD中，479胎接受染色体核型分析及CMA，基因检测显示60胎（60/479，12.53%）存在异常；134胎仅接受CMA，基因检测显示4胎（4/134，2.99%）存在异常。568胎为孤立性、45胎为非孤立性CHD，分别有40胎（40/568，7.04%）及15胎（15/45，33.33%）染色体核型分析和/或CMA显示异常。复合型CHD（10/41，24.39%）染色体核型分析和/或CMA异常检出率高于非复合型（54/572，9.44%）。复合型CHD中，染色体核型分析和/或CMA异常检出率在圆锥动脉干畸形（CTD）合并静脉系统畸形胎儿中最高，达30.77%（4/13）；非复合型CHD中，染色体核型分析和/或CMA异常检出率在内脏反位胎儿中最高，为25.00%（1/4）。染色体核型分析和/或CMA结果提示良性CNV或VUS的40胎中，WES提示3胎为致病性/可能致病性CNV（P/LP）、3胎为VUS、34胎为良性CNV。结论 CHD胎儿、尤其合并心外畸形者可能存在基因异常；CTD胎儿合并其他类型心脏结构异常时，基因异常可能性更大。相比单纯CMA，染色体核型分析联合CMA更有助于发现基因异常。

Prenatal ultrasonic diagnosis and genetic analysis of fetal congenital heart diseases

Objective To explore the genetic characteristics of fetuses with congenital heart diseases (CHD) diagnosed by prenatal ultrasound. Methods Data of 613 singletons with prenatal ultrasonic diagnosed CHD were retrospectively analyzed. The cardiac structural abnormalities were classified into 8 types. Whole-exome sequencing (WES) was performed for 40 fetuses since chromosomal karyotyping analysis and/or chromosomal microarray analysis (CMA) showed benign copy number variations (CNV) or variants of uncertain significance (VUS). Results Among 613 fetuses, 479 fetuses underwent both chromosomal karyotyping analysis and CMA, genomic abnormalities were detected in 60 fetuses (60/479, 12.53%). Among 134 fetuses underwent only CMA, genomic abnormalities were found in 4 fetuses (4/134, 2.99%). According to results of chromosomal karyotyping analysis and/or CMA, abnormalities were noticed in 40 fetuses (40/568, 7.04%) among 568 fetuses with isolated CHD, while in 15 fetuses (15/45, 33.33%) among 45 fetuses with non-isolated CHD, respectively. Abnormality detection rate of chromosomal karyotyping analysis and/or CMA in fetuses with complex CHD (10/41, 24.39%) was higher than that in fetuses with non-complex CHD (54/572, 9.44%). Among complex CHD fetuses, abnormality detection rate was the highest in fetuses with conotruncal defect (CTD) combined with malformation of venous system (4/13, 30.77%), while among fetuses with non-complex CHD, situs inversus viscerum had the highest detection rate (1/4, 25.00%). Among 40 fetuses chromosomal karyotyping analysis and/or CMA showed benign CNV or VUS, WES indicated pathogenic CNV/likely pathogenic CNV (P/LP) in 3 fetuses, VUS in 3 fetuses and benign CNV in 34 fetuses. Conclusion Fetuses with CHD, especially extracardiac malformations had possibilities of genomic abnormalities. Fetuses with CTD combined with malformation of venous system had higher possibilities of genomic abnormalities. Compared with CMA alone, chromosomal karyotyping analysis combined with CMA was helpful for detecting genomic abnormalities.