Yield of causative variants in hypertrophic cardiomyopathy (HCM) is increased in some probands, suggesting different clinical subgroups of disease occur. We hypothesized that a negative family history and no sarcomere mutations represent a nonfamilial subgroup of HCM. We sought to determine the prevalence, natural history, and potential clinical implications of this nonfamilial subgroup of HCM.

Four hundred and thirteen unrelated probands with HCM seen in a specialized HCM center between 2002 and 2015 and genetic testing performed were included in this retrospective cohort study. There were 251 (61%) probands with no reported family history of HCM, including 166 (40% of total) probands with no sarcomere mutation, that is, nonfamilial HCM. Quantified family pedigree data revealed no difference in mean number of first-degree relatives screened between nonfamilial and sarcomere-positive groups. Adjusted predictors of nonfamilial status were older age (odds ratio, 1.04; 95% confidence interval, 1.02–1.06; P=0.0001), male sex (odds ratio, 1.96; 95% confidence interval, 1.11–3.45; P=0.02), hypertension (odds ratio, 2.80; 95% confidence interval, 1.57–5.00; P=0.0005), and nonasymmetric septal morphology (odds ratio, 3.41; 95% confidence interval, 1.64–7.08; P=0.001). They had a less severe clinical course with greater event-free survival from major cardiac events (P=0.04) compared with sarcomere-positive HCM probands. Genotype prediction scores showed good performance in identifying genotype-positive patients (area under the curve, 0.71–0.75) and, in combination with pedigree characteristics, were further improved.

Approximately 40% of HCM probands have a nonfamilial subtype, with later onset and less severe clinical course. We propose a revised clinical pathway for management, highlighting the role of genetic testing, a detailed pedigree, and refined clinical surveillance recommendations for family members.