Exome Sequencing and Congenital Heart Disease in Sub-Saharan Africa.
Exome Sequencing and Congenital Heart Disease in Sub-Saharan Africa.
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撒哈拉以南非洲的外显子组测序和先天性心脏病。
DOI：
10.1161/circgen.120.003108
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发表时间：
2021-03
期刊：
影响因子：
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通讯作者：
Kruszka P
中科院分区：
文献类型：
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作者：
Ekure EN;Adeyemo A;Liu H;Sokunbi O;Kalu N;Martinez AF;Owosela B;Tekendo-Ngongang C;Addissie YA;Olusegun-Joseph A;Ikebudu D;Berger SI;Muenke M;Han Z;Kruszka P
先天性心脏病（CHD）是最常见的出生缺陷，约占全球人口的1%。在发展中国家有一些大型CHD测序项目，但在撒哈拉以南非洲没有。在这项外显子组测序研究中，我们招募了来自尼日利亚拉各斯的患有结构性心脏病的家庭。从尼日利亚的拉各斯招募了98名平均年龄为3.6岁的CHD患者。对先证者和父母（如有）进行外显子组测序。对于高度感兴趣的基因，我们使用基于心脏特异性RNA干扰（RNAi）的基因沉默系统在果蝇中进行了功能研究。最常见的三种CHD是法洛四联症（20%）、孤立性室间隔缺损（14%）和大动脉转位（8%）。10%的队列中存在已知导致CHD的致病或可能致病的基因变异。在64个完整的三人组中，我们发现了34个在gnomAD（v3）数据库中不存在于非洲人群中的新生变异。使用杂合蛋白质截短变体（shet）的选择效应的全基因组分布鉴定了19个功能丧失变体。9个基因在果蝇心脏中沉默时会导致显著的死亡率，包括4个以前与CHD无关的新疾病基因（UBB，EIF4G3，SREBF 1和胃L23）。这项研究确定了CHD的新候选基因和变异，并有助于与以前主要在欧洲队列中进行的CHD测序研究进行比较。这项研究是在研究不足的人群中进行CHD基因组研究的重要第一步。
Congenital heart disease (CHD) is the most common birth defect and affects roughly 1% of the global population. There have been a number of large CHD sequencing projects in developing countries, but none in sub-Saharan Africa. In this exome sequencing study, we recruited families from Lagos, Nigeria affected by structural heart disease. Ninety-eight participants with CHD and an average age of 3.6 years were recruited from Lagos, Nigeria. Exome sequencing was performed on probands, and parents when available. For genes of high interest, we conducted functional studies in Drosophila using a cardiac-specific RNA interference (RNAi)-based gene silencing system. The three most common CHDs were tetralogy of Fallot (20%), isolated ventricular septal defect (14%), and transposition of the great arteries (8%). Ten percent of the cohort had pathogenic or likely pathogenic variants in genes known to cause CHD. In 64 complete trios, we found 34 de novo variants that were not present in the African population in the gnomAD (v3) database. Nineteen loss of function variants were identified using the genome wide distribution of selection effects for heterozygous protein truncating variants (shet). Nine genes caused a significant mortality when silenced in the Drosophila heart, including 4 novel disease genes not previously associated with CHD (UBB, EIF4G3, SREBF1, and METTL23). This study identifies novel candidate genes and variants for CHD and facilitates comparisons with previous CHD sequencing studies in predominantly European cohorts. The study represents an important first step in genomic studies of CHD in under-studied populations.