BIO FOr CARE: biomarkers of hypertrophic cardiomyopathy development and progression in carriers of Dutch founder truncating MYBPC3 variants-design and status

Abstract

Background: Hypertrophic cardiomyopathy (HCM) is the most prevalent monogenic heart disease, commonly caused by truncating variants in the MYBPC3 gene. HCM is an important cause of sudden cardiac death; however, overall prognosis is good and penetrance in genotype-positive individuals is incomplete. The underlying mechanisms are poorly understood and risk stratification remains limited.

Aim: To create a nationwide cohort of carriers of truncating MYBPC3 variants for identification of predictive biomarkers for HCM development and progression.

Methods: In the multicentre, observational BIO FOr CARe (Identification of BIOmarkers of hypertrophic cardiomyopathy development and progression in Dutch MYBPC3 FOunder variant CARriers) cohort, carriers of the c.2373dupG, c.2827C > T, c.2864_2865delCT and c.3776delA MYBPC3 variants are included and prospectively undergo longitudinal blood collection. Clinical data are collected from first presentation onwards. The primary outcome constitutes a composite endpoint of HCM progression (maximum wall thickness ≥ 20 mm, septal reduction therapy, heart failure occurrence, sustained ventricular arrhythmia and sudden cardiac death).

Results: So far, 250 subjects (median age 54.9 years (interquartile range 43.3, 66.6), 54.8% male) have been included. HCM was diagnosed in 169 subjects and dilated cardiomyopathy in 4. The primary outcome was met in 115 subjects. Blood samples were collected from 131 subjects.

Conclusion: BIO FOr CARe is a genetically homogeneous, phenotypically heterogeneous cohort incorporating a clinical data registry and longitudinal blood collection. This provides a unique opportunity to study biomarkers for HCM development and prognosis. The established infrastructure can be extended to study other genetic variants. Other centres are invited to join our consortium.

Keywords: Biomarkers; Hypertrophic cardiomyopathy; MYBPC3; Prognosis.

Fig. 1

Schematic overview of the study design. The BIO FOr CARe (Identification of BIOmarkers of hypertrophic cardiomyopathy development and progression in Dutch MYBPC3 FOunder variant CARriers) study comprises an observational cohort of Dutch carriers of the c.2373dupG (p.Trp792fs), c.2827C > T (p.Arg943Ter), c.2864_2865delCT (p.Pro955fs) and c.3776delA (p.Gln1259fs) variants in the MYBPC3 gene. These variants are predicted to result in truncated mRNA with absence of truncated protein leading to haploinsufficiency. Subjects across the phenotypic spectrum associated with these variants are prospectively included for blood collection every 2 years and followed up over time. Clinical data are retrospectively collected from the first presentation onwards in a clinical registry to assess potential clinical predictors of disease penetrance and progression. HCM hypertrophic cardiomyopathy

Fig. 2

Flowchart showing the results of subject screening, as well as data on inclusion and blood collection. The reasons for exclusion are noted on the right for each stage. Requested local denotes subjects who requested blood collection in local cardiological centres. HTx heart transplantation