Qu Hui-Qi, Delfiner Matthew S, Gangireddy Chethan, Vaidya Anjali, Nguyen Kenny, Whitman Isaac R, Wang JuFang, Song Jianliang, Bristow Michael R, McTiernan Charles F, Gerhard Glenn S, Hakonarson Hakon, Feldman Arthur M
The Center for Applied Genomics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
Department of Medicine, Division of Cardiology, Lewis Katz School of Medicine at Temple University, Philadelphia, PA, USA.
J Mol Med (Berl). 2025 Feb;103(2):175-185. doi: 10.1007/s00109-024-02510-z. Epub 2024 Dec 27.
In one of the earliest reports from China during COVID-19, it was noted that over 20% of patients hospitalized with the disease had significant elevations of troponin, a marker of myocardial tissue damage, that put them at a higher risk. In a hypothesis-independent whole exome sequencing (WES) study in hospitalized COVID-19 patients of diverse ancestry, we observed putative enrichment in pathogenic variants in genes known to be involved in the pathogenesis of cardiomyopathy. This observation led us to hypothesize that the observed high morbidity and mortality in these patients might be due to the presence of rare genetic factors that had previously been silent but became relevant as a consequence of the severe stress inflicted by an infection with SARS-CoV-2. To test this hypothesis, we analyzed our WES data generated from a cohort of 325 patients sequentially admitted for COVID-19 infection. In this predominantly minority population (53.9% African ancestry and 37.9% Hispanic/Latin ancestry), our initial analysis screen identified 263 variants that were identified as highly deleterious (HD) from a total of 26,661 variants of interest that represented 215 genes. Of those, we identified 46 genes (in 58 patients) harboring rare HD coding variants that were previously implicated in dilated cardiomyopathy and were considered as disease initiators for the severe COVID-19 in this study. These findings offer valuable insights into the molecular mechanisms and genetic susceptibility to heart injury in severe COVID-19. KEY MESSAGES: COVID-19 may cause cardiac damage in some affected patients without a plausible biological explanation. Our study reveals an enrichment of highly deleterious variants linked to cardiomyopathy in severe COVID-19 patients. Genetic profiling unveils the molecular basis of severe COVID-19-related heart injury, potentially aiding in patient stratification.
在新冠疫情期间来自中国的最早一批报告中，有一份报告指出，因该疾病住院的患者中，超过20%的患者肌钙蛋白显著升高，肌钙蛋白是心肌组织损伤的标志物，这使他们面临更高的风险。在一项针对不同血统的新冠住院患者的非假设性全外显子组测序（WES）研究中，我们观察到已知参与心肌病发病机制的基因中，致病性变异存在推定富集。这一观察结果使我们推测，这些患者中观察到的高发病率和死亡率可能是由于存在罕见的遗传因素，这些因素以前处于沉默状态，但由于感染SARS-CoV-2造成的严重应激而变得相关。为了验证这一假设，我们分析了从325名因新冠感染而陆续入院的患者队列中生成的WES数据。在这个以少数族裔为主的人群（53.9%为非洲血统，37.9%为西班牙裔/拉丁裔血统）中，我们的初步分析筛查从总共26661个代表215个基因的感兴趣变异中，识别出263个被确定为高度有害（HD）的变异。其中，我们在58名患者中鉴定出46个基因，这些基因携带罕见的HD编码变异，这些变异先前与扩张型心肌病有关，在本研究中被视为重症新冠的疾病起始因素。这些发现为重症新冠患者心脏损伤的分子机制和遗传易感性提供了有价值的见解。关键信息：新冠可能在一些受影响的患者中导致心脏损伤，而没有合理的生物学解释。我们的研究揭示了重症新冠患者中与心肌病相关联的高度有害变异的富集。基因分析揭示了重症新冠相关心脏损伤的分子基础，可能有助于患者分层。
