In TPM1-related hypertrophic cardiomyopathy, additional sarcomeric variants increased the risk of death or cardiovascular hospitalization compared to a single TPM1 variant (45% vs. 7%).
Does phenotypic expression and the presence of additional sarcomeric variants increase the risk of mortality and cardiovascular hospitalizations in individuals with TPM1-related hypertrophic cardiomyopathy?
In individuals with TPM1-related hypertrophic cardiomyopathy, disease expression occurs in midlife with low penetrance, and adverse outcomes are strongly predicted by higher NT-proBNP, left atrial enlargement, older age, and the presence of additional sarcomeric variants.
Absolute Event Rate: 0% vs 0%
Abstract Background Sarcomeric Hypertrophic Cardiomyopathy (HCM) has variable genotypic and phenotypic expressions. Variants in the alpha-tropomyosin gene (TPM1) account for 1% to 5% of cases, but their clinical significance and role in disease progression remain poorly understood. Aim To characterize the phenotype and long-term outcome of individuals considered to have TPM1-related HCM. Methods Retrospective analysis of HCM patients followed in a tertiary center was performed, all carrying a TPM1 gene variant considered clinically as disease-related. However, conflicting classifications of pathogenicity may be at the stage. Clinical outcomes included a composite of all-cause mortality and cardiovascular hospitalizations. Results (Fig. 1) The cohort included 48 individuals from 15 unrelated families (out of 167 genotyped families with sarcomeric HCM), carrying a variant in the TPM1 gene. Only 2 different variants were identified: the p.Arg21Leu variant in 12 families (79%) and the p.Met281Val variant in 3 families (21%); 24 individuals had phenotypic expression (G+/Ph+), and the other 24 were only carriers (G+/Ph-). At diagnosis, HCM patients were older (48±3.9 vs. 35±3.2 years), with no gender differences between groups. At HCM diagnosis, LVOTO was present in 4 patients, the mean left atrial diameter (LAD) was 45±1.9 mm, and the maximum wall thickness was 17.7±1.1 mm. Over a median follow-up of 11.8 years (IQR 7.2–16.4), only 1 out of 24 patients G+/Ph- developed HCM. Among HCM patients, 25% showed episodes of non-sustained ventricular tachycardia, 5% had atrial fibrillation, and 4% developed a ventricular aneurysm. Two patients underwent septal reduction therapy, and two received an implantable cardioverter defibrillator for primary prevention of sudden cardiac death. The composite endpoint occurred in 21% of HCM patients. Adverse outcomes were significantly associated with higher NT-proBNP levels at diagnosis (3200 pg/mL vs. 377 pg/mL; p=0.019), larger LAD (51.4±4.3 mm vs. 43.3±2.0 mm; p=0.05), and older age (p=0.023). HCM patients had a six-fold increased risk of death or hospitalization compared to G+/Ph- individuals (OR 6.2; p=0.012). Patients who have also sarcomeric variants in other genes (even if currently classified as VUS) showed a higher incidence of the composite outcome compared with those carrying only the TPM1 single variant (45% vs. 7%; p=0.030). Conclusion In this Portuguese HCM cohort, TPM1 gene-related disease was more frequent than previously recognized, driven mainly by the p.Arg21Leu variant (79%). Disease expression occurred in midlife, with a variable phenotype and low penetrance. Key predictors of a worse prognosis included higher NT-proBNP levels, LA enlargement, older age at diagnosis and the presence of additional sarcomeric variants (even if classified currently as VUS). It is vital to reclassify variants regularly, and family cosegregation studies are a key part of translational medicine in this regard.
Vilela et al. (Sun,) reported a other. In TPM1-related hypertrophic cardiomyopathy, additional sarcomeric variants increased the risk of death or cardiovascular hospitalization compared to a single TPM1 variant (45% vs. 7%).