Genetics of dilated cardiomyopathy
- Ray E Hershberger, MD
Ray E Hershberger, MD
- Professor of Medicine (Cardiology and Human Genetics)
- Ohio State University
- Section Editors
- William J McKenna, MD
William J McKenna, MD
- Section Editor — Myopericardial Disease
- Professor of Cardiology
- University College, London
- Benjamin A Raby, MD, MPH
Benjamin A Raby, MD, MPH
- Section Editor — Genetics
- Associate Professor of Medicine
- Harvard Medical School
Dilated cardiomyopathy (DCM) is a common cause of heart failure (HF) and is the most common diagnosis in patients referred for cardiac transplantation. DCM is characterized by dilatation and systolic dysfunction of one or both ventricles. (See "Definition and classification of the cardiomyopathies".)
DCM is classified as idiopathic (idiopathic dilated cardiomyopathy, or IDC) when all recognized causes have been excluded. Potentially diagnosable causes of DCM include a variety of toxic, metabolic, or infectious agents. (See "Causes of dilated cardiomyopathy".) Ischemic heart disease must also be excluded. Although specialists commonly apply the diagnosis of IDC to DCMs of unknown cause, an etiology is present but undetected.
Family-based studies of first-degree relatives during the past few decades have established that familial dilated cardiomyopathy (known as familial DCM, or FDC) can be identified in 20 to 35 percent of patients diagnosed with IDC by clinical screening of family members. Most familial DCM is transmitted in an autosomal dominant inheritance pattern, although all inheritance patterns have been identified (autosomal recessive, X-linked, and mitochondrial). During the past 20 years, familial DCM genetic studies have identified mutations in more than 30 genes.
Most patients with genetic DCM will have an initial diagnosis of IDC. Given the frequency of familial DCM, evaluation of new IDC cases should include a careful three to four generation family history and clinical screening of first-degree family members as described below.
Developments have dramatically and favorably affected efforts to identify and understand the genetic basis of DCM, including the enormous impact of next generation sequencing (NGS), and the availability of very large databases of exome or genome sequences that can be used as reference sequences in gene discovery programs (eg, the Exome Study Project, Exome Variant Server, the Thousand Genomes Project, and the ExAC database). Extensive discovery studies over the past 20 years have identified rare variants in numerous genes.
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- GENES, PHENOTYPES, AND INHERITANCE
- Common phenotypes: autosomal dominant DCM with or without conduction system disease
- - DCM without conduction system disease
- Sarcomere genes
- Genes beyond the sarcomere
- - DCM with prominent conduction system disease
- - Peripartum cardiomyopathy
- - Other reports of DCM phenotypes
- X-linked transmission
- - Dystrophin gene mutations
- - Barth's syndrome
- Autosomal recessive transmission
- - Cardiomyopathy and sensorineural hearing loss
- - Rosenberg syndrome
- Autoimmune mechanisms
- Genetic testing for familial dilated cardiomyopathy
- NON-FAMILIAL DILATED CARDIOMYOPATHY