PDF(Pubmed)
Abstract：
Hypoplastic left heart syndrome (HLHS) is a severe congenital heart defect (CHD) characterized by hypoplasia of the left ventricle and aorta along with stenosis or atresia of the aortic and mitral valves. HLHS represents only ∼4%-8% of all CHDs but accounts for ∼25% of deaths. HLHS is an isolated defect (i.e., iHLHS) in 70% of families, the vast majority of which are simplex. Despite intense investigation, the genetic basis of iHLHS remains largely unknown. We performed exome sequencing on 331 families with iHLHS aggregated from four independent cohorts. A Mendelian-model-based analysis demonstrated that iHLHS was not due to single, large-effect alleles in genes previously reported to underlie iHLHS or CHD in >90% of families in this cohort. Gene-based association testing identified increased risk for iHLHS associated with variation in CAPN2 (p = 1.8 × 10-5), encoding a protein involved in functional adhesion. Functional validation studies in a vertebrate animal model (Xenopus laevis) confirmed CAPN2 is essential for cardiac ventricle morphogenesis and that in vivo loss of calpain function causes hypoplastic ventricle phenotypes and suggest that human CAPN2707C>T and CAPN21112C>T variants, each found in multiple individuals with iHLHS, are hypomorphic alleles. Collectively, our findings show that iHLHS is typically not a Mendelian condition, demonstrate that CAPN2 variants increase risk of iHLHS, and identify a novel pathway involved in HLHS pathogenesis.
摘要：
左心发育不良综合征（HLHS）是一种严重的先天性心脏病（CHD），其特征是左心室和主动脉发育不全以及主动脉瓣和二尖瓣狭窄或闭锁。HLHS仅占所有冠心病的4%-8%，但占死亡人数的25%。HLHS是一个孤立的缺陷(即，iHLHS)在70%的家庭中，其中绝大多数是单纯形的。尽管进行了激烈的调查，iHLHS的遗传基础在很大程度上仍然未知。我们对来自四个独立队列的331个iHLHS家庭进行了外显子组测序。基于孟德尔模型的分析表明，iHLHS不是由于单一，先前报道的基因中的大效应等位基因是iHLHS或CHD的基础，在该队列中>90％的家庭中。基于基因的关联测试确定了与CAPN2变异相关的iHLHS风险增加（p=1.8×10-5），编码参与功能粘附的蛋白质。在脊椎动物模型（非洲爪狼）中进行的功能验证研究证实，CAPN2对于心室形态发生至关重要，并且体内钙蛋白酶功能的丧失会导致心室发育不良表型，并表明人类CAPN2707C>T和CAPN21112C>T变体，每个人都在多个患有iHLHS的个体中发现，是低态等位基因。总的来说，我们的研究结果表明，iHLHS通常不是孟德尔疾病，证明CAPN2变体会增加iHLHS的风险，并确定涉及HLHS发病机制的新通路。
