Heart Center, Kuopio University Hospital, Kuopio, Finland.
Department of Medicine, Center for Medicine and Clinical Research, University of Eastern Finland, Kuopio University Hospital, P.O. Box 100, FIN-70029 KYS, Kuopio, Finland.
ESC Heart Fail. 2019 Apr;6(2):436-445. doi: 10.1002/ehf2.12420. Epub 2019 Feb 18.
Nationwide large-scale genetic and outcome studies in cohorts with hypertrophic cardiomyopathy (HCM) have not been previously published.
We sequenced 59 cardiomyopathy-associated genes in 382 unrelated Finnish patients with HCM and found 24 pathogenic or likely pathogenic mutations in six genes in 38.2% of patients. Most mutations were located in sarcomere genes (MYBPC3, MYH7, TPM1, and MYL2). Previously reported mutations by our study group (MYBPC3-Gln1061Ter, MYH7-Arg1053Gln, and TPM1-Asp175Asn) and a fourth major mutation MYH7-Val606Met accounted for 28.0% of cases. Mutations in GLA and PRKAG2 were found in three patients. Furthermore, we found 49 variants of unknown significance in 31 genes in 20.4% of cases. During a 6.7 ± 4.2 year follow-up, annual all-cause mortality in 482 index patients and their relatives with HCM was higher than that in the matched Finnish population (1.70 vs. 0.87%; P < 0.001). Sudden cardiac deaths were rare (n = 8). Systolic heart failure (hazard ratio 17.256, 95% confidence interval 3.266-91.170, P = 0.001) and maximal left ventricular wall thickness (hazard ratio 1.223, 95% confidence interval 1.098-1.363, P < 0.001) were independent predictors of HCM-related mortality and life-threatening cardiac events. The patients with a pathogenic or likely pathogenic mutation underwent an implantable cardioverter defibrillator implantation more often than patients without a pathogenic or likely pathogenic mutation (12.9 vs. 3.5%, P < 0.001), but there was no difference in all-cause or HCM-related mortality between the two groups. Mortality due to HCM during 10 year follow-up among the 5.2 million population of Finland was studied from death certificates of the National Registry, showing 269 HCM-related deaths, of which 32% were sudden.
We identified pathogenic and likely pathogenic mutations in 38% of Finnish patients with HCM. Four major sarcomere mutations accounted for 28% of HCM cases, whereas HCM-related mutations in non-sarcomeric genes were rare. Mortality in patients with HCM exceeded that of the general population. Finally, among 5.2 million Finns, there were at least 27 HCM-related deaths annually.
此前尚未发表过针对肥厚型心肌病（HCM）患者的全国性大规模遗传和预后研究。
我们对 382 名芬兰 HCM 患者的 59 个与心肌病相关的基因进行了测序，在 38.2%的患者中发现了 6 个基因中的 24 个致病性或可能致病性突变。大多数突变位于肌节基因（MYBPC3、MYH7、TPM1 和 MYL2）。本研究组之前报道的突变（MYBPC3-Gln1061Ter、MYH7-Arg1053Gln 和 TPM1-Asp175Asn）和第四个主要突变 MYH7-Val606Met 占病例的 28.0%。在 3 名患者中发现了 GLA 和 PRKAG2 的突变。此外，在 31 个基因中的 49 个未知意义的变异在 20.4%的病例中被发现。在 6.7±4.2 年的随访中，482 名索引患者及其 HCM 亲属的全因死亡率高于芬兰匹配人群（1.70 比 0.87%；P<0.001）。心脏性猝死很少见（n=8）。心力衰竭（危险比 17.256，95%置信区间 3.266-91.170，P=0.001）和最大左心室壁厚度（危险比 1.223，95%置信区间 1.098-1.363，P<0.001）是与 HCM 相关的死亡率和危及生命的心脏事件的独立预测因素。与没有致病性或可能致病性突变的患者相比，携带致病性或可能致病性突变的患者更常接受植入式心脏复律除颤器植入（12.9%比 3.5%，P<0.001），但两组之间的全因死亡率或与 HCM 相关的死亡率无差异。通过国家登记处的死亡证明研究芬兰 520 万人口中的 10 年 HCM 死亡率，共发现 269 例 HCM 相关死亡，其中 32%为猝死。
我们在 38%的芬兰 HCM 患者中发现了致病性和可能致病性突变。四个主要的肌节突变占 HCM 病例的 28%，而非肌节基因的 HCM 相关突变则很少见。HCM 患者的死亡率高于一般人群。最后，在 520 万芬兰人中，每年至少有 27 例 HCM 相关死亡。
