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

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.

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.

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.

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.