Next-generation sequencing in a series of 80 fetuses with complex cardiac malformations and/or heterotaxy
Next-generation sequencing in a series of 80 fetuses with complex cardiac malformations and/or heterotaxy
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DOI：
10.1002/humu.24132
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发表时间：
2020-11-10
期刊：
影响因子：
3.9
通讯作者：
Bouvagnet, Patrice
中科院分区：
文献类型：
--
作者：
Liu, Hui;Giguet-Valard, Anna-Gaelle;Bouvagnet, Patrice
在此，我们报告了一系列80个胎儿先天性心脏病（CHD）和/或异位和无细胞遗传学异常的基因的大面板的筛选。男性49例（61%/39%），有家族史28例（35%），无父母血缘关系77例（96%）。除1例胎儿合并先天性心脏病外，其余均为复杂先天性心脏病，其中52例（65%）胎儿合并先天性心脏病。共29例（36%）有心外和心外异位畸形。在10/80例（12.5%）病例中发现致病变异，异位组（8/52例，15%）的百分比高于非异位组（2/28例，7%），心外和心外畸形3例（3/29，10%）。遗传方式为6对隐性基因（DNAI 1、GDF 1、MMP 21、MYH 6、NEK 8和ZIC 3）和2对显性基因（SHH和TAB 2）。在3例中发现了纯合致病性变异，其中仅1例具有已知的血缘关系。总之，在剔除有细胞遗传学异常的胎儿后，下一代测序在12.5%的CHD和/或异位症胎儿病例中发现了因果变异。对未来怀孕的遗传咨询大大改善。令人惊讶的是，意外的血缘关系占20%的病例与确定的致病性变异。
Herein, we report the screening of a large panel of genes in a series of 80 fetuses with congenital heart defects (CHDs) and/or heterotaxy and no cytogenetic anomalies. There were 49 males (61%/39%), with a family history in 28 cases (35%) and no parental consanguinity in 77 cases (96%). All fetuses had complex CHD except one who had heterotaxy and midline anomalies while 52 cases (65%) had heterotaxy in addition to CHD. Altogether, 29 cases (36%) had extracardiac and extra-heterotaxy anomalies. A pathogenic variant was found in 10/80 (12.5%) cases with a higher percentage in the heterotaxy group (8/52 cases, 15%) compared with the non-heterotaxy group (2/28 cases, 7%), and in 3 cases with extracardiac and extra-heterotaxy anomalies (3/29, 10%). The inheritance was recessive in six genes (DNAI1, GDF1, MMP21, MYH6, NEK8, and ZIC3) and dominant in two genes (SHH and TAB2). A homozygous pathogenic variant was found in three cases including only one case with known consanguinity. In conclusion, after removing fetuses with cytogenetic anomalies, next-generation sequencing discovered a causal variant in 12.5% of fetal cases with CHD and/or heterotaxy. Genetic counseling for future pregnancies was greatly improved. Surprisingly, unexpected consanguinity accounts for 20% of cases with identified pathogenic variants.