Hypertrophic Cardiomyopathy – The Impact of Age at Diagnosis of the Proband on Genetic Yield, Clinical Presentation, Outcomes, and Yield of Family Screening

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Abstract Background Hypertrophic cardiomyopathy (HCM) is a complex disease with variable clinical presentation and familial impact. Age at diagnosis may influence phenotypic expression, but it is unclear if age also affects clinical outcomes, genetic findings, and yield of family screening. Methods Retrospective cohort study of families screened for HCM in Eastern Denmark (2006-2023). Probands were analyzed by age at diagnosis both continuously and in quartiles: 18-45, 46-56, 57-65, and >65 years. Results 612 probands (62% male, median 56 years, median follow-up 9 years) and 919 relatives (45% male, median 42 years) were studied. A higher proband age at diagnosis was associated with more left ventricular (LV) outflow tract obstruction (OR 1.19/10-years), hypertension (OR 1.57/10-years) and atrial fibrillation (OR 1.24/10-years), but less LV hypertrophy (wall thickness ≥30 mm, OR 0.52/10-years), and ventricular arrhythmias (OR 0.81/10-years). Older age at diagnosis was associated with higher all-cause mortality, but similar cardiovascular mortality. Sarcomere variants were less common in the oldest versus youngest quartile of probands (13 vs. 42%, p<0.001). The yield of family screening at baseline was higher in probands diagnosed younger (OR 1.34 per 10-year decrease). Long-term HCM incidence in relatives was not associated with proband age at diagnosis, and overall yield of family screening was comparable across all proband ages at diagnosis. Conclusions The probands age at HCM diagnosis influenced clinical and genetic findings but the cardiovascular mortality and the yield of family screening were similar across all ages at diagnosis, supporting the presently recommended follow-up and family screening irrespective of the probands age at diagnosis. Clinical perspectives What is new? The study demonstrates that the age at diagnosis in HCM probands is significantly associated with distinct clinical and genetic profiles. It provides novel insights into family screening yield, revealing that despite differences in baseline genetic yield and clinical presentation across age groups, the overall prevalence and incidence of HCM in relatives remain similar regardless of the proband’s age at diagnosis. What are the clinical implications? These findings support the recommendation for consistent family screening in HCM, regardless of the age at which the proband is diagnosed, as the risk for developing HCM appears comparable across all age groups. The identification of age-related differences in clinical phenotype and genetic findings could inform tailored risk stratification and management strategies, potentially enhancing personalized care for HCM patients.

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