Founder mutation in myosin-binding protein C with an early onset and a high penetrance in males

Abstract

Objective: One of the challenges in hypertrophic cardiomyopathy (HCM) is to determine the pathogenicity of genetic variants and to establish genotype/phenotype correlations. This study aimed to: (1) demonstrate that MYBPC3 c.2149-1G>A is a founder pathogenic variant, (2) describe the phenotype and clinical characteristics of mutation carriers and (3) compare these patients with those with the most frequent pathogenic HCM variants: MYBPC3 p.Arg502Trp/Gln.

Methods: We reviewed genetic tests performed in HCM probands at our institution. We carried out transcript analyses to demonstrate the splicing effect, and haplotype analyses to support the founder effect of MYBPC3 c.2149-1G>A. Carriers with this mutation were compared with those from MYBPC3 p.Arg502Trp/Gln in terms of presentation features, imaging and outcomes.

Results: MYBPC3 c.2149-1G>A was identified in 8 of 570 probands and 25 relatives. Penetrance was age and sex dependent, 50.0% of the carriers over age 36 years and 75.0% of the carriers over 40 years showing HCM. Penetrance was significantly higher in males: in carriers older than 30 years old, 100.0% of males vs 50.0% of females had a HCM phenotype (p=0.01). Males were also younger at diagnosis (32±13 vs 53±10 years old, p<0.001). MYBPC3 c.2149-1G>A resulted in an abnormal transcript that led to haploinsufficiency and was segregated in two haplotypes. However, both came from one founder haplotype. Affected carriers showed a better functional class and higher left ventricular ejection fraction (LVEF) than patients with MYBPC3 p.Arg502Trp/Gln (p<0.05 for both). Nevertheless, the rate of major adverse outcomes was similar between the two groups.

Conclusions: MYBPC3 c.2149-1G>A splicing variant is a founder mutation. Affected males show an early onset of HCM and with higher penetrance than women. Carriers show better functional class and higher LVEF than MYBPC3 p.Arg502Trp/Gln carriers, but a similar rate of major adverse outcomes.

Keywords: cardiomyopathy; diagnostic imaging; genetics; hypertrophic.

Figure 1

MYBPC3 c.2149-1G>A pedigrees. Symbols denote sex, genetic and disease status: +, carriers; –, non-carriers; ?, unknown phenotype; box, male; circle, female; darkened, affected; slashed, deceased; clear symbol, unaffected; without sign, not studied. SD, sudden death.

Figure 2

Penetrance. Comparison between MYBP3 c.2149–1G>A and MYBPC3 p.Arg502Trp/Gln variants and between sex for each variant. (A) Full study population. (B) MYBP3 c.2149–1G>A sex analysis. (C) MYBPC3 p.Arg502Trp/Gln sex analysis. HCM, hypertrophic cardiomyopathy.

Figure 3

Cardiac MR (CMR) images showing phenotype variability in MYBPC3 c.2149-1G>A carriers. (A–D) CMR images of two brothers: A, B is a 48-year-old female carrier with normal phenotype and C, D is her 49-year-old affected brother with septal hypertrophy of 22 mm and extensive LGE. (E, F) CMR images showing a severe left ventricle hypertrophy with extensive LGE in a 21-year-old carrier with severe systolic disfunction. (G, H) CMR images showing a restrictive phenotype with severe atrial enlargement and fibrosis. LGE, late gadolinium enhancement.

Figure 4

Survival free from major clinical outcomes. Comparison between MYBPC3 c.2149–1G>A and MYBPC3 p.Arg502Trp/Gln variants.

Figure 5

Haplotype reconstruction analysis. (A) phylogeny reconstruction of MYBPC3 haplotypes. Tree Neighbor-Joining in MEGA7. (B) segregation of H52 and H53 haplotypes in a family carrying MYBPC3 c.2149–1G>A.