Genotype/phenotype analysis of dilated and hypertrophic cardiomyopathy due to troponin complex variants in Newfoundland and Labrador families

Abstract Background/Objectives: Hypertrophic (HCM) and dilated cardiomyopathy (DCM) are inherited cardiomyopathies (prevalences 1:500 and 1:250 respectively). TNNI3 p.R162Q and TNNT2 p.ΔK210 are autosomal dominant pathogenic variants causing HCM and DCM respectively. Using large NL families segregating TNNI3 p.R162Q and TNNT2 p.ΔK210, this study will explore the penetrance, age of onset and severity of disease. Methods: Six NL families have one or both variants with 79 affected (40 TNNI3 p.R162Q heterozygous, five TNNI3 p.R162Q homozygous, two TNNT2 p.ΔK210 heterozygotes, three double heterozygous) and 31 unaffected. All clinical cardiac tests were collected. Kaplan-Meier survivorship curves and cox regression analyses were performed using SPSS v.30. Results: Twenty-three TNNI3 p.R162Q heterozygotes had clinical abnormalities, twelve had none. Median age for first clinical abnormality or SCD for affected individuals was 54yrs and 63yrs for unaffected (p=0.014, HR:2.684). Median age for affected males was 41yrs and 57yrs for females (p=0.019, HR:2.254). Two double heterozygotes show no structural signs of disease, the third had no cardiac concerns. TNNT2 p.ΔK210 heterozygotes have early, severe disease. TNNI3 p.R162Q homozygotes have highly variable phenotypes. Conclusion: The cardiac phenotypes of TNNI3 p.R162Q heterozygotes and TNNI3 p.R162Q homozygotes are highly variable. Disease presents earlier in heterozygous males. TNNT2 p.ΔK210 phenotype is severe. Double heterozygotes have mild/no phenotype.