Hypertrophic cardiomyopathy in myosin-binding protein C (MYBPC3) Icelandic founder mutation carriers

• Type of Material: Article
• Authors: Berglind Adalsteinsdottir, University of Iceland; Michael Burke, Emory University; Barry J. Maron, Tufts University; Ragnar Danielsen, Landspitali - The National University Hospital of Iceland; Begona Lopez, University of Navarra; Javier Diez, University of Navarra; Petr Jarolim, Brigham and Women's Hospital; Jonathan Seidman, Harvard Medical School; Christine E. Seidman, Harvard Medical School; Carolyn Y. Ho, Brigham and Women's Hospital; Gunnar Th. Gunnarsson, University of Iceland
• Language: English
• Date: 2020-04-05
• Publisher: BMJ Publications
• Publication Version: Final Published Version
• Copyright Statement: © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1136/openhrt-2019-001220
• Title of Journal or Parent Work: Open Heart
• Volume: 7
• Issue: 1
• Start Page: e001220
• End Page: e001220
• Grant/Funding Information: This study was supported by the Howard Hughes Medical Institute (CES), the National Institutes of Health (5HL084553: CES, JGS; 1P20HL101408: CYH; 1P50HL112349: CYH), Akureyri Hospital Research Fund (GTG), Landspitali–The National University Hospital of Iceland Research Fund (BA), the Icelandic Cardiac Society Research Fund (GTG).
• Keywords: Sarcomeres; Carrier Proteins; Mutation; Genetic Predisposition to Disease; Female; Phenotype; Male; Hemodynamics; Humans; Founder Effect; Penetrance; Heredity; Ventricular Function, Left; Cardiomyopathy, Hypertrophic; genetics; Ventricular Remodeling; Iceland; Middle Aged; Aged; Cross-Sectional Studies; Risk Factors; cardiomyopathy hypertrophic; Age of Onset; Pedigree; Adult; echocardiography; Heterozygote
• Research Categories: Health Sciences, Public Health; Biology, Genetics; Health Sciences, Pathology; Health Sciences, Human Development

Abstract

Objective: The myosin-binding protein C (MYBPC3) c.927-2A>G founder mutation accounts for >90% of sarcomeric hypertrophic cardiomyopathy (HCM) in Iceland. This cross-sectional observational study explored the penetrance and phenotypic burden among carriers of this single, prevalent founder mutation. Methods: We studied 60 probands with HCM caused by MYBPC3 c.927-2A>G and 225 first-degree relatives. All participants underwent comprehensive clinical evaluation and relatives were genotyped. Results: Genetic and clinical evaluation of relatives identified 49 genotype-positive (G+) relatives with left ventricular hypertrophy (G+/LVH+), 59 G+without LVH (G+/LVH-) and 117 genotype-negative relatives (unaffected). Compared with HCM probands, G+/LVH+ relatives were older at HCM diagnosis, had less LVH, a less prevalent diastolic dysfunction, fewer ECG abnormalities, lower serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) and high-sensitivity cardiac troponin I levels, and fewer symptoms. The penetrance of HCM was influenced by age and sex; specifically, LVH was present in 39% of G+males but only 9% of G+females under age 40 years (p=0.015), versus 86% and 83%, respectively, after age 60 (p=0.89). G+/LVH- subjects had normal wall thicknesses, diastolic function and NT-proBNP levels, but subtle changes in LV geometry and more ECG abnormalities than their unaffected relatives. Conclusions: Phenotypic expression of the Icelandic MYBPC3 founder mutation varies by age, sex and proband status. Men are more likely to have LVH at a younger age, and disease manifestations were more prominent in probands than in relatives identified via family screening. G+/LVH- individuals had subtle clinical differences from unaffected relatives well into adulthood, indicating subclinical phenotypic expression of the pathogenic mutation.