P1770A MYBPC3 founder splicing mutation with high penetrance and early onset of Hypertrophic Cardiomyopathy in men

Abstract

Introduction MYBPC3 is the most frequently affected gene in Hypertrophic Cardiomyopathy (HCM). This study aimed to analyze the founder origin and clinical phenotype of the MYBPC3 c.2149–1G>A pathogenic variant, which had been previously described in only one HCM proband. Methods HCM probands who underwent genetic test at our institution were reviewed. Clinical data from carriers were collected retrospectively. In order to identify the haplotypes sharing MYBPC3 c.2149–1G>A variant, six markers covering from 46 to 62 Mb of HSA11 were genotyped in 11 carriers and 6 non-carriers. Genotype information for those markers was extracted for Iberian population (n=107) from the 1000 Genomes Browser database. Haplotypes were reconstructed with Phase 2.1 software and phylogenetic analysis with MEGA7 software. Results MYBPC3 c.2149–1G>A was identified in 7 of 523 HCM probands and 23 family members. Penetrance in carriers older than 30 years was 80% (100% men, 55% women, p=0.03). Men were significantly younger at diagnoses, with larger left atrium. One patient had an aborted sudden death. The haplotype reconstruction showed the existence of 53 haplotypes. The most probable segregation for MYBPC3 c.2149–1G>A carriers was estimated in two haplotypes, H52 and H53. The phylogeny reconstruction estimated that both H52 and H53 haplotypes may come from common ancestor H16. In fact, H52 comes from one recombination event in H53 haplotype that has recently occurred in one of our families. Characteristics of affected carriers All (n=16) Men (n=11) Women (n=5) p Age at diagnoses (years) 44 (19) 38 (22) 48 (14.5) 0.036 Maximal LVWT (mm) 19 (4) 19 (3) 17 (6) 0.209 Ejection Fraction (%) 61 (5) 61 (4) 68 (17) 0.131 Left atrium (mm) 42 (13) 44 (15) 35 (11) 0.05 Outflow Tract Obstruction 2 (12.5%) 2 (18.2%) 0 (0%) 0.524 Late Gadolinium Enhancement† 13 (92.9%) 9 (90.0%) 4 (100%) 0.714 Dyspnea (NYHA ≥2) 4 (25%) 4 (36.4%) 0 (0%) 0.242 NSVT 6 (37.5%) 4 (36.4%) 2 (40%) 0.538 Atrial Fibrillation 4 (25%) 3 (27.3%) 1 (20%) 0.635 ICD primary/secondary prevention 7 (43.8%)/1 (6.3%) 5 (45.5%)/1 (9.1%) 2 (40%)/0 (0.0%) 0.750 Data are expressed as median (interquartile range) or number (%). LVWT: left ventricular wall thickness; NSVT: non sustained ventricular tachycardia. †14 man and 4 women underwent cardiac magnetic resonance. MYBPC3 haplotype tree. Conclusions MYBPC3 c.2149–1G>A is a founder pathogenic variant that shows a high penetrance and an early onset of HCM, specially in men.