Doedens Anne, Skarp Sini, Holmström Lauri, Pakanen Lasse, Saarimäki Samu, Kerkelä Risto, Pylkäs Katri, Huikuri Heikki V, Junttila Juhani
Faculty of Medicine, University of Oulu, Oulu, Finland.
Faculty of Medicine, University of Oulu, Oulu, Finland
Heart. 2024 Dec 23;111(2):55-61. doi: 10.1136/heartjnl-2024-324623.
Hypertrophic cardiomyopathy is a common cause of non-ischaemic sudden cardiac death (SCD). Left ventricular hypertrophy (LVH) without cardiomyopathy-related myocardial disarray is a common autopsy finding and is often associated with prior hypertension in SCD subjects. Our aim was to investigate novel rare gene variants among SCD subjects with presumably hypertension-related LVH and myocardial fibrosis at autopsy.
Whole exome sequencing was used to study rare variants (minor allele frequency<0.005) estimated to be deleterious in 96 non-ischaemic SCD subjects with presumably hypertension-related LVH and myocardial fibrosis. Associations of the identified variants with cardiac disease endpoints were replicated in the Finnish national genetic study (FinnGen) dataset.
18 variants were estimated likely to affect protein function and 14 of these were associated with cardiomyopathies, heart failure, conduction abnormalities, hypertension and/or cardiac arrest in Finnish population (FinnGen). Three of the variants were classified as pathogenic or likely pathogenic. These include the splice site variant NM_000449.3:c.234-1G>A in regulatory factor X5 and frameshift variants NM_000449.3:c.234-1G>A in dehydrogenase/reductase 7C and NM_015873.3:c.1164del in villin like.
We identified rare deleterious variants associated with LVH in SCD subjects. Several of the identified rare variants associated with cardiovascular endpoints including heart failure, cardiomyopathies, cardiac arrest and hypertension in general population.
肥厚型心肌病是非缺血性心源性猝死（SCD）的常见原因。左心室肥厚（LVH）而无心肌病相关的心肌紊乱是常见的尸检发现，且在SCD患者中常与既往高血压有关。我们的目的是研究尸检时可能与高血压相关的LVH和心肌纤维化的SCD患者中的新型罕见基因变异。
采用全外显子组测序研究96例非缺血性SCD患者中估计有害的罕见变异（次要等位基因频率<0.005），这些患者可能患有与高血压相关的LVH和心肌纤维化。在芬兰国家基因研究（FinnGen）数据集中复制已鉴定变异与心脏病终点的关联。
18个变异估计可能影响蛋白质功能，其中14个与芬兰人群（FinnGen）中的心肌病、心力衰竭、传导异常、高血压和/或心脏骤停有关。其中3个变异被分类为致病性或可能致病性。这些包括调节因子X5中的剪接位点变异NM_000449.3:c.234-1G>A以及脱氢酶/还原酶7C中的移码变异NM_000449.3:c.234-1G>A和绒毛蛋白样蛋白中的NM_015873.3:c.1164del。
我们在SCD患者中鉴定出与LVH相关的罕见有害变异。在一般人群中，几个已鉴定的罕见变异与包括心力衰竭、心肌病、心脏骤停和高血压在内的心血管终点相关。
