Spanish founder variant in MYBPC3: implications of diagnostic criteria, clinical phenotype, and prognosis.

INTRODUCTION AND OBJECTIVES: MYBPC3 is the most frequently mutated gene in hypertrophic cardiomyopathy (HCM). This study presents the clinical phenotype of a founder variant in MYBPC3, p.Arg891Alafs*160, present in 47 families from southern Spain, and compares it with other described founder truncating variants in MYBPC3. METHODS: We studied 259 relatives of 47 index cases with HCM carrying the p.Arg891Alafs*160 variant. Clinical evaluation, including recently proposed diagnostic criteria, pedigree analysis and genotyping in relation to outcomes, were performed. RESULTS: A total of 159 carriers of p.Arg891Alafs*160 (age, 48.8 ± 19.6 years; 40.3% female) were identified, of whom 90 (57.0%, 30.0% female) had HCM. The mean age of affected individuals was 57.1 ± 15.0 years, mean maximal left ventricular hypertrophy (LVH) was 19.0 ± 5.7 mm, and 20 (22.5%) had left ventricular obstruction. Age, sex and body surface area correction altered the proportion of men and women with HCM. There were 8 adverse cardiac events: 1 sudden death, 1 resuscitated cardiac arrest, 2 implantable cardioverter-defibrillator discharges, 2 transplants, and 2 heart failure deaths. Disease penetrance increased with age, and men developed disease 8.0 years earlier than women. This variant had a lower annual sudden death rate than other MYBPC3 truncating variants. CONCLUSIONS: MYBPC3 p.Arg891Alafs*160 is a founder truncating variant associated with HCM. Affected carriers present with incomplete penetrance, moderate LVH, and disease onset in middle age. Implementation of age, sex and body surface area-normalized LVH cutoffs for the diagnosis of HCM has an impact on the proportion of affected females.