Genetics of congenital heart disease: the glass half empty.
Genetics of congenital heart disease: the glass half empty.
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DOI：
10.1161/circresaha.112.300853
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发表时间：
2013-02-15
影响因子：
20.1
通讯作者：
Seidman CE
中科院分区：
文献类型：
--
作者：
Fahed AC;Gelb BD;Seidman JG;Seidman CE
先天性心脏病（CHD）是新生儿最常见的先天性畸形。在多种实验动物模型中，通过干扰在涉及肌细胞特化、分化或心脏形态发生的发育途径中起作用的选定分子，已经产生了心脏畸形。相比之下，人类这些扰动的精确遗传、表观遗传或环境基础仍然知之甚少。在过去的几十年里，研究人员试图通过对罕见的孟德尔CHD家族进行常规的全基因组分析和对CHD队列中的候选基因进行测序来弥合这一知识差距。虽然产生很少的，通常是高度渗透的疾病基因突变，这些发现提供了三个显着的见解。首先，人类CHD突变影响了一组协调心脏发育的异质分子。其次，CHD突变通常会改变基因/蛋白质剂量。第三，相同的致病性CHD突变导致各种不同的畸形，这意味着更高阶的相互作用占特定的CHD表型。包括SNP阵列、下一代测序和CNV平台在内的当代基因组技术的出现正在加速CHD遗传原因的发现。重要的是，这些方法能够研究散发病例，这是CHD最常见的表现。正在进行的基因组研究的新结果验证了早期从单基因CHD家族中获得的观察结果。在这篇综述中，我们将探讨如何继续使用这些技术和系统生物学的整合，预计将扩大我们对冠心病遗传结构的理解。
Congenital heart disease (CHD) is the most common congenital anomaly in newborn babies. Cardiac malformations have been produced in multiple experimental animal models, by perturbing selected molecules that function in the developmental pathways involved in myocyte specification, differentiation or cardiac morphogenesis. In contrast, the precise genetic, epigenetic or environmental basis for these perturbations in humans remains poorly understood. Over the past few decades, researchers have tried to bridge this knowledge gap through conventional genome-wide analyses of rare Mendelian CHD families and by sequencing candidate genes in CHD cohorts. While yielding few, usually highly penetrant, disease gene mutations, these discoveries provided three notable insights. First, human CHD mutations impact a heterogeneous set of molecules that orchestrate cardiac development. Second, CHD mutations often alter gene/protein dosage. Third, identical pathogenic CHD mutations cause a variety of distinct malformations, implying that higher order interactions account for particular CHD phenotypes. The advent of contemporary genomic technologies including SNP arrays, next-generation sequencing, and CNV platforms are accelerating the discovery of genetic causes of CHD. Importantly, these approaches enable study of sporadic cases, the most common presentation of CHD. Emerging results from ongoing genomic efforts have validated earlier observations learned from the monogenic CHD families. In this review, we explore how continued use of these technologies and integration of systems biology is expected to expand our understanding of the genetic architecture of CHD.