Arrington Cammon B, Bleyl Steven B, Brunelli Luca, Bowles Neil E
Department of Pediatrics (Cardiology) University of Utah School of Medicine, Eccles Institute of Human Genetics, 15 North 2030 East, Room 7110B, Salt Lake City, UT 84112, USA.
Future Cardiol. 2013 Jul;9(4):507-18. doi: 10.2217/fca.13.40.
Congenital heart defects (CHDs) are the most common congenital abnormalities. Analysis of large multigenerational families has led to the identification of a number of genes for CHDs. However, identifiable variations in these genes are the cause of a small proportion of cases of CHDs, suggesting significant genetic heterogeneity. In addition, large families with CHDs are rare, making the identification of additional genes difficult. Next-generation sequencing technologies will provide an opportunity to identify more genes in the future. However, the significant genetic variation between individuals will present a challenge to distinguish between 'pathogenic' and 'benign' variants. We have demonstrated that the analysis of multiple individuals in small families using combinations of algorithms can reduce the number of candidate variants to a small, manageable number. Thus, the analysis of small nuclear families or even distantly related 'sporadic' cases may begin to uncover the 'dark matter' of CHD genetics.
先天性心脏缺陷（CHD）是最常见的先天性异常。对大型多代家庭的分析已导致鉴定出一些与CHD相关的基因。然而，这些基因中可识别的变异仅导致一小部分CHD病例，这表明存在显著的遗传异质性。此外，患有CHD的大型家庭很少见，这使得鉴定其他基因变得困难。下一代测序技术将为未来鉴定更多基因提供机会。然而，个体之间显著的遗传变异将对区分“致病”和“良性”变异构成挑战。我们已经证明，使用算法组合对小家庭中的多个个体进行分析可以将候选变异的数量减少到一个小的、可管理的数量。因此，对小型核心家庭甚至远亲“散发”病例的分析可能开始揭示CHD遗传学的“暗物质”。
