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Penetrance of Hypertrophic Cardiomyopathy in Sarcomere Protein Mutation Carriers

Lorenzini, M; Norrish, G; Field, E; Ochoa, JP; Cicerchia, M; Akhtar, MM; Syrris, P; ... Elliott, PM; + view all (2020) Penetrance of Hypertrophic Cardiomyopathy in Sarcomere Protein Mutation Carriers. Journal of the American College of Cardiology , 76 (5) pp. 550-559. 10.1016/j.jacc.2020.06.011. Green open access

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Abstract

BACKGROUND: Predictive genetic screening of relatives of patients with hypertrophic cardiomyopathy (HCM) caused by sarcomere protein (SP) gene mutations is current standard of care, but there are few data on long-term outcomes in mutation carriers without HCM. OBJECTIVES: The aim of this study was to determine the incidence of new HCM diagnosis in SP mutation carriers. METHODS: This was a retrospective analysis of adult and pediatric SP mutation carriers identified during family screening who did not fulfill diagnostic criteria for HCM at first evaluation. RESULTS: The authors evaluated 285 individuals from 156 families (median age 14.2 years [interquartile range: 6.8 to 31.6 years], 141 [49.5%] male individuals); 145 (50.9%) underwent cardiac magnetic resonance (CMR). Frequency of causal genes was as follows: MYBPC3 n ¼ 123 (43.2%), MYH7 n ¼ 69 (24.2%), TNNI3 n ¼ 39 (13.7%), TNNT2 n ¼ 34 (11.9%), TPM1 n ¼ 9 (3.2%), MYL2 n ¼ 6 (2.1%), ACTC1 n ¼ 1 (0.4%), multiple mutations n ¼ 4 (1.4%). Median follow-up was 8.0 years (interquartile range: 4.0 to 13.3 years) and 86 (30.2%) patients developed HCM; 16 of 50 (32.0%) fulfilled diagnostic criteria on CMR but not echocardiography. Estimated HCM penetrance at 15 years of follow-up was 46% (95% confidence interval [CI]: 38% to 54%). In a multivariable model adjusted for age and stratified for CMR, independent predictors of HCM development were male sex (hazard ratio [HR]: 2.91; 95% CI: 1.82 to 4.65) and abnormal electrocardiogram (ECG) (HR: 4.02; 95% CI: 2.51 to 6.44); TNNI3 variants had the lowest risk (HR: 0.19; 95% CI: 0.07 to 0.55, compared to MYBPC3). CONCLUSIONS: Following a first negative screening, approximately 50% of SP mutation carriers develop HCM over 15 years of follow-up. Male sex and an abnormal ECG are associated with a higher risk of developing HCM. Regular CMR should be considered in long-term screening.

Type: Article
Title: Penetrance of Hypertrophic Cardiomyopathy in Sarcomere Protein Mutation Carriers
Location: United States
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.jacc.2020.06.011
Publisher version: https://doi.org/10.1016/j.jacc.2020.06.011
Language: English
Additional information: This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
UCL classification: UCL
UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science > Clinical Science
URI: https://discovery.ucl.ac.uk/id/eprint/10106549
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