Theis Jeanne L, Olson Timothy M
Cardiovascular Genetics Research Laboratory, Mayo Clinic, Rochester, MN 55905, USA.
Department of Pediatric and Adolescent Medicine, Division of Pediatric Cardiology, Mayo Clinic, Rochester, MN 55905, USA.
J Cardiovasc Dev Dis. 2022 Apr 15;9(4):117. doi: 10.3390/jcdd9040117.
Hypoplastic left heart syndrome (HLHS) is a genetically complex disorder. Whole genome sequencing enables comprehensive scrutiny of single nucleotide variants and small insertions/deletions, within both coding and regulatory regions of the genome, revolutionizing susceptibility-gene discovery research. Because millions of rare variants comprise an individual genome, identification of alleles linked to HLHS necessitates filtering algorithms based on various parameters, such as inheritance, enrichment, omics data, known genotype-phenotype associations, and predictive or experimental modeling. In this brief review, we highlight family and cohort-based strategies used to analyze whole genome sequencing datasets and identify HLHS candidate genes. Key findings include compound and digenic heterozygosity among several prioritized genes and genetic associations between HLHS and bicuspid aortic valve or cardiomyopathy. Together with findings of independent genomic investigations, has emerged as a compelling disease gene for HLHS and other left-sided congenital heart diseases.
左心发育不全综合征（HLHS）是一种遗传复杂性疾病。全基因组测序能够全面检测基因组编码区和调控区内的单核苷酸变异以及小的插入/缺失，彻底改变了易感基因发现研究。由于数百万种罕见变异构成了个体基因组，因此鉴定与HLHS相关的等位基因需要基于各种参数的过滤算法，如遗传方式、富集情况、组学数据、已知的基因型-表型关联以及预测或实验模型。在这篇简短的综述中，我们重点介绍了用于分析全基因组测序数据集并鉴定HLHS候选基因的基于家系和队列的策略。主要发现包括几个优先基因中的复合杂合性和双基因杂合性，以及HLHS与二叶式主动脉瓣或心肌病之间的遗传关联。与独立基因组研究的结果一起， 已成为HLHS和其他左侧先天性心脏病的一个令人信服的疾病基因。
