LaHaye Stephanie, Corsmeier Don, Basu Madhumita, Bowman Jessica L, Fitzgerald-Butt Sara, Zender Gloria, Bosse Kevin, McBride Kim L, White Peter, Garg Vidu
From the Center for Cardiovascular Research, The Research Institute (S.L., M.B., S.F.-B., G.Z., K.B., K.L.M., V.G.), The Heart Center (S.L., M.B., J.L.B., S.F.-B., K.L.M., V.G.), and Biomedical Genomics Core and the Center for Microbial Pathogenesis, The Research Institute (D.C., P.W.), Nationwide Children's Hospital, Columbus, OH; and Department of Molecular Genetics (S.L., V.G.) and Department of Pediatrics (J.L.B., S.F.-B., K.L.M., P.W., V.G.), The Ohio State University, Columbus.
Circ Cardiovasc Genet. 2016 Aug;9(4):320-9. doi: 10.1161/CIRCGENETICS.115.001324. Epub 2016 Jul 14.
Congenital heart disease (CHD) is the most common type of birth defect with family- and population-based studies supporting a strong genetic cause for CHD. The goal of this study was to determine whether a whole exome sequencing (WES) approach could identify pathogenic-segregating variants in multiplex CHD families.
WES was performed on 9 kindreds with familial CHD, 4 with atrial septal defects, 2 with patent ductus arteriosus, 2 with tetralogy of Fallot, and 1 with pulmonary valve dysplasia. Rare variants (<1% minor allele frequency) that segregated with disease were identified by WES, and variants in 69 CHD candidate genes were further analyzed. These selected variants were subjected to in silico analysis to predict pathogenicity and resulted in the discovery of likely pathogenic mutations in 3 of 9 (33%) families. A GATA4 mutation in the transactivation domain, p.G115W, was identified in familial atrial septal defects and demonstrated decreased transactivation ability in vitro. A p.I263V mutation in TLL1 was identified in an atrial septal defects kindred and is predicted to affect the enzymatic functionality of TLL1. A disease-segregating splice donor site mutation in MYH11 (c.4599+1delG) was identified in familial patent ductus arteriosus and found to disrupt normal splicing of MYH11 mRNA in the affected individual.
Our findings demonstrate the clinical utility of WES to identify causative mutations in familial CHD and demonstrate the successful use of a CHD candidate gene list to allow for a more streamlined approach enabling rapid prioritization and identification of likely pathogenic variants from large WES data sets.
URL: https://clinicaltrials.gov; Unique Identifier: NCT0112048.
先天性心脏病（CHD）是最常见的出生缺陷类型，基于家庭和人群的研究支持CHD存在强大的遗传病因。本研究的目的是确定全外显子测序（WES）方法能否在多个CHD家庭中识别出致病性分离变异。
对9个患有家族性CHD的家系进行了WES，其中4个家系患有房间隔缺损，2个家系患有动脉导管未闭，2个家系患有法洛四联症，1个家系患有肺动脉瓣发育异常。通过WES鉴定出与疾病分离的罕见变异（次要等位基因频率<1%），并对69个CHD候选基因中的变异进行了进一步分析。对这些选定的变异进行了计算机分析以预测致病性，结果在9个家系中的3个（33%）发现了可能的致病突变。在家族性房间隔缺损中鉴定出转录激活域中的GATA4突变p.G115W，并在体外证明其转录激活能力降低。在一个房间隔缺损家系中鉴定出TLL1中的p.I263V突变，预计该突变会影响TLL1的酶功能。在家族性动脉导管未闭中鉴定出MYH11中的一个疾病分离剪接供体位点突变（c.4599+1delG），并发现该突变会破坏受影响个体中MYH11 mRNA的正常剪接。
我们的研究结果证明了WES在识别家族性CHD致病突变方面的临床实用性，并证明了成功使用CHD候选基因列表可采用更简化的方法，以便从大型WES数据集中快速优先排序并识别可能的致病变异。
