Cardiovascular Genetics Research Laboratory (J.L.T., R.S.S., T.M.O.), Mayo Clinic, Rochester, MN.
Division of Pediatric Cardiology, Department of Pediatric and Adolescent Medicine (T.N., D.J.H., T.M.O.), Mayo Clinic, Rochester, MN.
Circ Genom Precis Med. 2022 Apr;15(2):e003523. doi: 10.1161/CIRCGEN.121.003523. Epub 2022 Feb 8.
Whole-genome sequencing in families enables deciphering of congenital heart disease causes. A shared genetic basis for familial bicuspid aortic valve (BAV) and hypoplastic left heart syndrome (HLHS) was postulated.
Whole-genome sequencing was performed in affected members of 6 multiplex BAV families, an HLHS cohort of 197 probands and 546 relatives, and 813 controls. Data were filtered for rare, predicted-damaging variants that cosegregated with familial BAV and disrupted genes associated with congenital heart disease in humans and mice. Candidate genes were further prioritized by rare variant burden testing in HLHS cases versus controls. Modifier variants in HLHS proband-parent trios were sought to account for the severe developmental phenotype.
In 5 BAV families, missense variants in 6 ontologically diverse genes for structural (, , and ) and signaling (, , and ) proteins fulfilled filtering metrics. , encoding cadherin epidermal growth factor laminin G seven-pass G-type receptor, was identified as a candidate gene in 2 families and was the only gene demonstrating rare variant enrichment in HLHS probands (=0.003575). HLHS-associated variants included 16 missense, one splice site, and 3 noncoding variants predicted to disrupt canonical transcription factor binding sites, most of which were inherited from a parent without congenital heart disease. Filtering whole-genome sequencing data for rare, predicted-damaging variants inherited from the other parent revealed 2 cases of compound heterozygosity, one case of - synergistic heterozygosity, and 4 cases of - digenic heterozygosity.
is a susceptibility gene for familial BAV and HLHS, further implicating planar cell polarity pathway perturbation in congenital heart disease.
对家族进行全基因组测序可用于解析先天性心脏病的病因。有人假设，二叶式主动脉瓣（BAV）和左心发育不全综合征（HLHS）的家族性疾病存在共同的遗传基础。
对 6 个多例 BAV 家族的受影响成员、197 名 HLHS 先证者和 546 名亲属以及 813 名对照进行全基因组测序。对与家族性 BAV 共分离并破坏与人类和小鼠先天性心脏病相关基因的罕见、预测性有害变异进行数据过滤。通过 HLHS 病例与对照之间的罕见变异负担测试，对候选基因进行进一步的优先级排序。在 HLHS 先证者-父母三体型中寻找修饰变体，以解释严重的发育表型。
在 5 个 BAV 家族中，6 个结构（、、和）和信号（、、和）蛋白的 6 个不同本体论的错义变体符合过滤标准。编码钙粘蛋白-表皮生长因子-层粘连蛋白 G 七通 G 型受体的 基因在 2 个家族中被确定为候选基因，并且是唯一在 HLHS 先证者中显示罕见变异富集的基因（=0.003575）。与 HLHS 相关的变体包括 16 个错义、1 个剪接位点和 3 个非编码变体，这些变体预计会破坏典型的转录因子结合位点，其中大多数变体是从没有先天性心脏病的父母那里遗传来的。对来自另一个父母的罕见、预测性有害变体进行全基因组测序数据过滤，发现了 2 例 复合杂合性、1 例 协同杂合性和 4 例 双基因杂合性。
是家族性 BAV 和 HLHS 的易感基因，进一步提示平面细胞极性途径的扰动与先天性心脏病有关。
