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

• Main Authors: Adalsteinsdottir, B. (Berglind), Burke, M. (Michael), Maron, B.J. (Barry J.), Danielsen, R. (Ragnar), López, B. (Begoña), Diez, J. (Javier), Jarolim, P. (Petr), Seidman, J.G. (J.G.), Seidman, C.E. (Christine E.), Ho, C.Y. (Carolyn Y.), Gunnarsson, G.T. (Gunnar Th)
• Format: Article in Journal/Newspaper
• Language: English
• Published: British Medical Journals 2020
• Subjects: Cardiomyopathy hypertrophic; Iceland; Myosin-binding protein C (MYBPC3); Echocardiography; Genetics
• Online Access: https://hdl.handle.net/10171/65191

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.