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Nonfamilial Hypertrophic Cardiomyopathy: Prevalence, Natural History, and Clinical Implications
Jodie Ingles1, Charlotte Burns1, Richard D Bagnall1
1From the Agnes Ginges Centre for Molecular Cardiology, Centenary Institute, Sydney, New South Wales, Australia (J.I., C.B., R.D.B., L.L., L.Y., T.S., C.S.); Central Clinical School (J.I., C.B., R.D.B., R.P., C.S.), and School of Public Health (T.D.), Sydney Medical School, University of Sydney, Australia; Department of Cardiology, Royal Prince Alfred Hospital, Sydney, Australia (J.I., C.B., L.Y., R.P., C.S.); School of Population Health, Faculty of Medicine, Dentistry and Health Sciences, The University of Western Australia, Perth (T.B.); Department of Cardiology, Royal Brisbane & Women's Hospital, Australia (J.J.A.); and School of Medicine, University of Queensland, Brisbane, Australia (J.J.A.).
Insights
Approximately 40% of hypertrophic cardiomyopathy (HCM) patients have a nonfamilial form. This subtype presents later and has a less severe clinical course, suggesting revised management strategies are needed.
Area of Science:
- Cardiology
- Genetics
- Personalized Medicine
Background:
- Hypertrophic cardiomyopathy (HCM) exhibits variable clinical presentations, suggesting distinct etiological subgroups.
- A subset of HCM probands presents with no family history and lacks sarcomere mutations, indicating a potentially nonfamilial form of the disease.
Purpose of the Study:
- To determine the prevalence and natural history of nonfamilial HCM.
- To identify clinical predictors and implications of this nonfamilial HCM subgroup.
Main Methods:
- Retrospective cohort study of 413 unrelated HCM probands undergoing genetic testing.
- Analysis of family pedigrees, clinical data, and genetic testing results.
- Statistical analysis to identify predictors and compare clinical outcomes.
Main Results:
- Nonfamilial HCM (no family history, no sarcomere mutation) was identified in 40% of probands.
- Predictors included older age, male sex, hypertension, and nonasymmetric septal morphology.
- Nonfamilial HCM showed a less severe clinical course with improved event-free survival compared to sarcomere-positive HCM.
Conclusions:
- A significant nonfamilial subtype of HCM exists, characterized by later onset and milder disease.
- Revised clinical management pathways are proposed, integrating genetic testing, detailed family history, and tailored surveillance.
- This identifies a distinct clinical subgroup warranting specific diagnostic and management approaches.
Background:
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.
Methods And Results:
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.
Conclusions:
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.