Abstract

Aims: Nationwide large‐scale genetic and outcome studies in cohorts with hypertrophic cardiomyopathy (HCM) have not been previously published.

Methods and results: 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.

Conclusions: 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.

Acknowledgements The FinHCM Study Group: Helena Kervinen10 (Hyvinkää Hospital, Hyvinkää, Finland), Juha Mustonen11 (North Karelia Central Hospital, Joensuu, Finland), Jukka Juvonen12 (Kainuu Central Hospital, Kajaani, Finland), Mari Niemi13 (Kokkola Central Hospital, Kokkola, Finland), Paavo Uusimaa14 (Oulu University Hospital, Oulu, Finland), Juhani Junttila14 (Oulu University Hospital, Oulu, Finland), Matti Kotila15 (Seinäjoki Central Hospital, Seinäjoki, Finland), Mikko Pietilä16 (Turku University Hospital, Turku, Finland), Heini Jyrkilä17 (University of Eastern Finland, Kuopio, Finland), Ilkka Mähönen18 (University of Tampere, Tampere, Finland), Paula Vartia19 (University of Helsinki, Helsinki, Finland).