Development, Aging and Regeneration Program, Center for Genetic Disorders & Aging Research, Sanford Burnham Prebys Medical Discovery Institute, San Diego, United States.
Department of Bioengineering, Sanford Consortium for Regenerative Medicine, UCSD, School of Medicine, San Diego, United States.
Elife. 2023 Jul 5;12:e83385. doi: 10.7554/eLife.83385.
Hypoplastic left heart syndrome (HLHS) is a severe congenital heart disease (CHD) with a likely oligogenic etiology, but our understanding of the genetic complexities and pathogenic mechanisms leading to HLHS is limited. We performed whole genome sequencing (WGS) on 183 HLHS patient-parent trios to identify candidate genes, which were functionally tested in the heart model. Bioinformatic analysis of WGS data from an index family of a HLHS proband born to consanguineous parents prioritized 9 candidate genes with rare, predicted damaging homozygous variants. Of them, cardiac-specific knockdown (KD) of mitochondrial MICOS complex subunit resulted in drastically compromised heart contractility, diminished levels of sarcomeric actin and myosin, reduced cardiac ATP levels, and mitochondrial fission-fusion defects. These defects were similar to those inflicted by cardiac KD of ATP synthase subunits of the electron transport chain (ETC), consistent with the MICOS complex's role in maintaining cristae morphology and ETC assembly. Five additional HLHS probands harbored rare, predicted damaging variants in or . Hypothesizing an oligogenic basis for HLHS, we tested 60 additional prioritized candidate genes from these patients for genetic interactions with in sensitized fly hearts. Moderate KD of in combination with (activator of RNA polymerase II), (, E3 ubiquitin ligase), or ( scaffolding protein) caused synergistic heart defects, suggesting the likely involvement of diverse pathways in HLHS. Further elucidation of novel candidate genes and genetic interactions of potentially disease-contributing pathways is expected to lead to a better understanding of HLHS and other CHDs.
左心发育不全综合征（HLHS）是一种严重的先天性心脏病（CHD），可能具有寡基因病因，但我们对导致 HLHS 的遗传复杂性和发病机制的理解有限。我们对 183 个 HLHS 患者-父母三对进行了全基因组测序（WGS），以鉴定候选基因，并在心脏模型中对其进行了功能测试。对来自 HLHS 先证者的近亲父母指数家族的 WGS 数据进行生物信息学分析，优先考虑了 9 个具有罕见、预测有害纯合变异的候选基因。其中，MICOS 复合物亚基的心脏特异性敲低（KD）导致心肌收缩力严重受损，肌动蛋白和肌球蛋白的水平降低，心脏 ATP 水平降低，线粒体裂变融合缺陷。这些缺陷与电子传递链（ETC）的 ATP 合酶亚基的心脏 KD 造成的缺陷相似，与 MICOS 复合物在维持嵴形态和 ETC 组装中的作用一致。另外 5 名 HLHS 先证者在 或 中携带罕见的、预测有害的变异。假设 HLHS 的多基因基础，我们在敏感的果蝇心脏中测试了来自这些患者的另外 60 个优先候选基因与 之间的遗传相互作用。 与 （RNA 聚合酶 II 的激活剂）、 （E3 泛素连接酶）或 （支架蛋白）的中度 KD 导致协同的心脏缺陷，表明 HLHS 中可能涉及多种途径。对潜在疾病相关途径的新候选基因和遗传相互作用的进一步阐明有望更好地理解 HLHS 和其他 CHD。
