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Epidemiology of the inherited cardiomyopathies

Nature Reviews Cardiology volume 18, pages 22–36 (2021)Cite this article

Subjects

Abstract

In the absence of contemporary, population-based epidemiological studies, estimates of the incidence and prevalence of the inherited cardiomyopathies have been derived from screening studies, most often of young adult populations, to assess cardiovascular risk or to detect the presence of disease in athletes or military recruits. The global estimates for hypertrophic cardiomyopathy (1/500 individuals), dilated cardiomyopathy (1/250) and arrhythmogenic right ventricular cardiomyopathy (1/5,000) are probably conservative given that only individuals who fulfil diagnostic criteria would have been included. This caveat is highly relevant because a substantial minority or even a majority of individuals who carry disease-causing genetic variants and are at risk of disease complications have incomplete and/or late-onset disease expression. The genetic literature on cardiomyopathy, which is often focused on the identification of genetic variants, has been biased in favour of pedigrees with higher penetrance. In clinical practice, an abnormal electrocardiogram with normal or non-diagnostic imaging results is a common finding for the sarcomere variants that cause hypertrophic cardiomyopathy, the titin and sarcomere variants that cause dilated cardiomyopathy and the desmosomal variants that cause either arrhythmogenic right ventricular cardiomyopathy or dilated cardiomyopathy. Therefore, defining the genetic epidemiology is also challenging given the overlapping phenotypes, incomplete and age-related expression, and highly variable penetrance even within individual families carrying the same genetic variant.

Key points

  • Contemporary age-adjusted and sex-adjusted, population-based epidemiological studies of the incidence and prevalence of the inherited cardiomyopathies are lacking.

  • Contemporary understanding of the genetic epidemiology of the inherited cardiomyopathies reveals incomplete and age-related disease expression and low penetrance for the majority of the genetic variants associated with these conditions.

  • Current prevalence estimates for hypertrophic cardiomyopathy (1/500) and dilated cardiomyopathy (1/250) are on the basis of screening studies, mainly in healthy young adults, and probably underestimate the true prevalence of disease and the risk of disease-related complications.

  • Prevalence estimates for arrhythmogenic cardiomyopathy (1/2,000 to 1/5,000) are on the basis of extrapolation from allele frequencies of genetic variants and the generally low penetrance of most of these variants.

  • Inherited restrictive cardiomyopathy is rare and usually associated with hypertrophic, dilated, infiltrative or arrhythmic cardiomyopathy, sometimes with musculoskeletal abnormalities in other members of the family.

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Fig. 1: Male patient aged 19 years with hypertrophic cardiomyopathy.
Fig. 2: Penetrance and disease expression vary between genes and between pathogenic variants.
Fig. 3: Echocardiographic evaluation at initial screening and during follow-up of asymptomatic relatives of probands with DCM.
Fig. 4: Prevalence of truncating variants in TTN in comparison with the prevalence of inherited forms of cardiomyopathy.

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Acknowledgements

The authors are supported by a grant from the Leducq Foundation (W.J.M. and D.P.J.).

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Authors and Affiliations

  1. Institute of Cardiovascular Science, University College London, London, UK

    William J. McKenna

  2. Heart Hospital, Hamad Medical Corporation, Doha, Qatar

    William J. McKenna

  3. Section of Advanced HF & Transplant Cardiology, Medical University of South Carolina, Charleston, SC, USA

    Daniel P. Judge

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Correspondence to William J. McKenna.

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Competing interests

D.P.J. has received payments as a consultant from 4D Molecular Therapeutics, ADRx Pharma and Pfizer, and has received research funding from Array Biopharma and Eidos Therapeutics. W.J.M. declares no competing interests.

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ClinVar: https://www.ncbi.nlm.nih.gov/clinvar/

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Supplementary information

Glossary

Mendelian pattern

Inheritance pattern of single-gene disorders with high penetrance, including autosomal dominant, autosomal recessive and X-linked.

Incomplete disease expression

A genetic predisposition to a disease that does not cause manifestations that are sufficient to meet the criteria for diagnosis of the condition.

Age-related penetrance

A genetic predisposition that does not cause phenotypic manifestations until later in life.

Epsilon waves

A feature of the electrocardiogram defined as a reproducible low-amplitude signal between the end of the QRS complex and the onset of the T wave in the right precordial leads (V1 to V3).

Variants of uncertain significance

DNA variants that do not meet criteria for being classified as pathogenic, likely pathogenic, benign or likely benign, according to the joint recommendation of the American College of Medical Genetics and the Association for Molecular Pathology.

Desmosome

Subcellular structures mediating intercellular junctions for many types of cell, particularly cardiomyocytes.

Haplotype

Sets of chromosomal markers for sections of DNA that segregate in families.

Digenic heterozygosity

The presence of one pathogenic variant in each of two different genes, each of which contributes to the phenotype.

Oligogenic inheritance

A constellation of more than two DNA variants, each of which contributes to the phenotype.

Allele frequency

The number of times that a variant is present in a large population divided by the total number of copies of all variants at that particular locus.

Hypertrabeculation

An increased ratio of non-compacted to compacted areas of the left ventricle; also referred to as non-compaction.

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McKenna, W.J., Judge, D.P. Epidemiology of the inherited cardiomyopathies. Nat Rev Cardiol 18, 22–36 (2021). https://doi.org/10.1038/s41569-020-0428-2

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