MYBPC3 c.927-2A>G carriers had higher IVSd (12.7mm vs 9.8mm), reduced basal septal strain (-12% vs -15%), smaller LV cavity, larger left atria, and elevated pro-BNP.
Does the MYBPC3 c.927-2A>G mutation alter echocardiographic parameters and Pro-BNP levels in carriers without a clinical hypertrophic cardiomyopathy diagnosis compared to non-carriers?
A significant proportion of previously undiagnosed MYBPC3 c.927-2A>G mutation carriers exhibit underlying echocardiographic and biomarker abnormalities indicative of cardiomyopathy.
Abstract Background The MYBPC3 c.927-2AG founder mutation is responsible for 95% of sarcomeric hypertrophic cardiomyopathy (HCM) in Iceland and has an estimated population prevalence of 0.36% (1:280). Of ~1200 predicted carriers only ~200 have been identified in previous studies, leaving the vast majority of carriers with unknown clinical status. Sudden cardiac death (SCD) is sometimes the first symptom of HCM and HCM is one of the most common cause of SCD in young people. The disease course can be altered with appropriate therapy, which emphasises the importance of detecting individuals at risk. Purpose To improve the understanding of genotype-phenotype relationship of the MYBPC3 c.927-2AG mutation and ultimately provide more efficient care, including SCD prevention. Methods This is a population-based genotype-based recall study on MYBPC3 c.927-2AG carriers without a clinical HCM diagnosis (G+). It is based on data from 166,281 genotyped Icelanders participating in research studies at deCODE genetics, of whom 561 carried the mutation. 126 had a previous HCM diagnosis and were excluded from the study and 92 were deceaced. The remaining 343 G+ were invited to particitate as well as a control group of age and sex matched genotype-negative individuals (G-, n=350). Medical records were reviewed to confirm that none of the G+ participants had a previous HCM diagnosis. In this first part of the study, all participants underwent echocardiography and B-type natriuretic peptide (BNP) measurement. Results 68% participated (468 of 679), the mean age was 56 years and 60% were females. Results from the echocardiography showed that interventricular septum diameter in diastole (IVSd) was larger in G+ individuals than G- (p-value= 9.4x10-29, mean IVSd: 12.7mm in G+ vs 9.8mm in G-). 53 G+ (23%) had IVSd 15mm but none G-. One of the G+ had IVSd 30mm. Strain imaging showed reduced basal septal strain values in G+ compared to G- (p-value=1.4x10-10, mean strain: -12% in G+ vs -15% in G-). G+ had a smaller left ventricular internal diameter in end diastole than G- (p-value=2.9x10-9, mean LVIDd: 45.0 mm in G+ vs 47.9mm in G-) and larger left atrial volume index (p-value=2.71x10-10, mean LAESV index: 28.5 mL/m² in G+ vs 23.5 mL/m² in G-). Pro-BNP was higher in G+ than G- (p-value=2.8x10-14, G+ 0.58 SD. higher than G-). Conclusions Based on recall-by genotype data, previously undiagnosed carriers of the MYBPC3 c.927-2AG mutation had increased IVSd, reduced basal septal strain values, smaller left ventricular cavity and larger left atria compared to non-carriers. Pro-BNP values were also higher among G+. This study demonstrates that a significant proportion of previously undiagnosed carriers have underlying cardiomyopathy that may have clinical consequences. The results highlight the need for identification and disclosure of actionable genotypes. Further examinations of participants including ambulatory ECG monitoring and CMR will enable further risk stratification.Participants Interventricular septal diameter
Gunnarsdottir et al. (2025) studied this question. MYBPC3 c.927-2A>G carriers had higher IVSd (12.7mm vs 9.8mm), reduced basal septal strain (-12% vs -15%), smaller LV cavity, larger left atria, and elevated pro-BNP.