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Genetics of idiopathic dilated cardiomyopathy
E Arbustini1, P Morbini, A Pilotto
1Pathology Department, IRCCS Policlinico S. Matteo, Pavia, Italy. e.arbustini@smatteo.pv.it diagnostica.molecolare@smatteo.pv.it
Insights
Diagnosing familial dilated cardiomyopathy (DCM) relies on screening relatives and reviewing medical records. Molecular diagnostics are advancing for specific genetic defects like dystrophin, offering crucial insights for affected families.
Area of Science:
- Cardiology
- Genetics
- Molecular Biology
Background:
- Familial dilated cardiomyopathy (DCM) diagnosis requires evidence-based screening of relatives and deceased individuals.
- Most DCM pedigrees follow autosomal inheritance; X-linked and matrilinear forms are rare, and autosomal recessive inheritance is challenging to assess.
- Current knowledge of familial DCM genetics is limited, with few cases benefiting from molecular diagnosis.
Purpose of the Study:
- To outline the evidence-based diagnostic approach for familial dilated cardiomyopathy.
- To review known genetic causes and inheritance patterns of familial DCM.
- To highlight the importance and current status of molecular diagnostics in familial DCM.
Main Methods:
- Clinical and echocardiographic screening of family members.
- Review of clinical reports for deceased relatives.
- Linkage analysis and candidate gene screening for genetic defects.
Main Results:
- Familial DCM diagnosis integrates clinical data, family history, and genetic analysis.
- Identified genetic links to dystrophin defects, glycoprotein-associated dystrophin (DAG) defects, mitochondrial DNA/nuclear gene defects, actin, and desmin.
- Clinical screening identifies familial forms, preclinical cases, and inheritance patterns.
Conclusions:
- Evidence-based diagnosis of familial DCM is crucial for affected families.
- Molecular diagnosis is becoming increasingly feasible for specific genetic defects, aiding carrier detection and understanding inheritance.
- Continued research is needed to expand molecular diagnostic capabilities for familial DCM.
Abstract:
Familial dilated cardiomyopathy (DCM) should be an "evidence-based" diagnosis derived from clinical and echocardiographic screening of informed and consenting relatives of index patients, and on the examination of clinical reports for deceased relatives. Most familial dilated cardiomyopathy pedigrees show an autosomal pattern of inheritance. Very few of them are X-linked and matrilinear. Autosomal recessive inheritance is difficult to be assessed in an evidence-based setting. By linkage analysis, several loci, but no disease gene, have been identified. At present, few cases of familial dilated cardiomyopathy can benefit of a molecular diagnosis. The diagnosis of dystrophin defect-related dilated cardiomyopathy is important for patients and families, especially for carrier detection. These patients present X-linked inheritance, dominant cardiac involvement and raised levels of serum creatine phosphokinase. Defects of the glycoprotein complex associated to dystrophin (DAG) are rare skeletal muscle diseases with possible cardiac involvement. Mitochondrial diseases, both pure cardiomyopathies and multiorgan syndromes involving the heart, are associated to defects of mitochondrial DNA genes or of nuclear genes coding for mitochondrial proteins. Barth's syndrome develops in male children with granulocytopenia, dilated cardiomyopathy, and methylglutaconic aciduria. Cardiomyopathies with atrioventricular block are observed in hemochromatosis, Emery-Dreifuss syndrome, desmin storage disease, and in isolated familial dilated cardiomyopathy. Actin defects were recently identified in 2 unrelated patients with familial dilated cardiomyopathy. Desmin defects were also recently identified in 1 familial dilated cardiomyopathy. The overall knowledge, although in progression, is still limited. Clinical family screening identifies familial forms, preclinical cases, and inheritance pattern. By candidate gene screening, the molecular diagnosis can be provided for dystrophin, DAG, mitochondrial DNA, actin and desmin gene defects.