Abstract

Introduction: The occurrence of hypertrophic cardiomyopathy (HCM) in relatives to HCM index patients with a normal genetic investigation of recognized HCM genes is largely unknown. It was the aim to determine the number of relatives with HCM among index patients with a normal genetic investigation. Methods: Clinical and genetic investigations were performed in consecutive index patients with HCM. Genetic investigations by next-generation sequencing were made in 116 recognized and likely HCM genes, and sequence variants were classified according to American College of Medical Genetics and Genomics criteria. First-degree relatives were invited for clinical investigations, including echocardiography and ECG-recording. Results: A total of 453 HCM index patients underwent clinical and genetic investigations, of whom 60% (270/453) did not carry pathogenic/likely pathogenic variants. Clinical investigations in 751 of their relatives identified 38 relatives (5%) who fulfilled HCM diagnostic criteria, and during five years of follow-up, two relatives developed HCM. In 88% of families (237/270), no relatives were affected. Affected relatives were older than healthy relatives, (56 years vs. 44 years p<0.01), characterized by more comorbidity in terms of treatment for hypertension (31% vs. 18% p=0.05) and more frequently had coronary heart disease (14% vs. 1% p<0.01). Risk calculations of sudden cardiac death were low (<4%/5 years) in 76% (29/38) of affected relatives based on the European Society of Cardiology recommendations. Six relatives were considered at high risk of SCD and received a prophylactic implantable cardioverter-defibrillator (ICD), but none experienced any ICD shock therapy. Adverse events were observed in four affected relatives; three experienced SCD, and one developed end-stage heart failure. Conclusions: HCM index patients with normal genetic investigations rarely had affected relatives. Those affected were older at disease onset and had more comorbidity, suggesting that inheritance is polygenic/multifactorial. Discontinuation of follow-up could be considered in unaffected families, as disease development among healthy relatives was rarely seen, and few experienced adverse disease complications and sudden death.

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