Molecular Genetics and Complex Inheritance of Congenital Heart Disease.
Molecular Genetics and Complex Inheritance of Congenital Heart Disease.
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DOI：
10.3390/genes12071020
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发表时间：
2021-06-30
期刊：
影响因子：
3.5
通讯作者：
Jin SC
中科院分区：
文献类型：
--
作者：
Diab NS;Barish S;Dong W;Zhao S;Allington G;Yu X;Kahle KT;Brueckner M;Jin SC
先天性心脏病（CHD）是最常见的先天性畸形，也是其中的主要死亡原因。据估计，90%的CHD病例是由遗传病因引起的，但到目前为止，高达55%的患者的分子诊断仍未得到解决。拷贝数变异和非整倍体占总体病例的约23%，高通量基因组技术已经揭示了CHD中其他类型的遗传变异。通过高通量测序确定的第一个CHD风险基因型是从头突变，其中许多发生在染色质修饰基因中。心脏发生的小鼠模型进一步支持染色质修饰CHD突变的破坏性质。通过对人群规模的CHD队列进行测序也鉴定了传播突变，并且许多传播突变在纤毛基因和Notch或VEGF途径基因中富集。虽然我们在确定冠心病的病因方面已经取得了很大进展，但需要做更多的工作来结束所有冠心病家庭的诊断之旅。CHD的复杂遗传学解释正在出现，但需要越来越复杂的分析策略应用于非常大的CHD队列，然后才能为遗传学未解决的患者提供分子诊断。在这篇综述中，我们讨论了冠心病的遗传结构和生物学途径参与其发病机制。
Congenital heart disease (CHD) is the most common congenital malformation and the leading cause of mortality therein. Genetic etiologies contribute to an estimated 90% of CHD cases, but so far, a molecular diagnosis remains unsolved in up to 55% of patients. Copy number variations and aneuploidy account for ~23% of cases overall, and high-throughput genomic technologies have revealed additional types of genetic variation in CHD. The first CHD risk genotypes identified through high-throughput sequencing were de novo mutations, many of which occur in chromatin modifying genes. Murine models of cardiogenesis further support the damaging nature of chromatin modifying CHD mutations. Transmitted mutations have also been identified through sequencing of population scale CHD cohorts, and many transmitted mutations are enriched in cilia genes and Notch or VEGF pathway genes. While we have come a long way in identifying the causes of CHD, more work is required to end the diagnostic odyssey for all CHD families. Complex genetic explanations of CHD are emerging but will require increasingly sophisticated analysis strategies applied to very large CHD cohorts before they can come to fruition in providing molecular diagnoses to genetically unsolved patients. In this review, we discuss the genetic architecture of CHD and biological pathways involved in its pathogenesis.
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