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[Genetic diagnosis of familial dilated cardiomyopathy]
Michele Pasotti1, Alessandra Repetto, Angela Pisani
1Dipartimento di Cardiologia, IRCCS Policlinico San Matteo, Pavia.
Insights
Familial dilated cardiomyopathy (DCM) affects 25-30% of cases and requires family screening. Genetic research is complex due to high heterogeneity, necessitating interdisciplinary collaboration for better diagnosis.
Area of Science:
- Cardiology
- Genetics
- Molecular Biology
Context:
- Familial dilated cardiomyopathy (DCM) is clinically defined by at least two affected family members, with a prevalence of 25-30%.
- Current diagnostic approaches involve clinical, non-invasive screening of family members of index patients.
- Familial DCM exhibits diverse inheritance patterns (autosomal dominant, recessive, X-linked, matrilinear) and genetic heterogeneity.
Purpose:
- To summarize the clinical and genetic landscape of familial dilated cardiomyopathy.
- To highlight the challenges and needs in diagnosing and understanding familial DCM.
- To emphasize the importance of interdisciplinary approaches in familial DCM research.
Summary:
- Familial DCM is clinically defined by affected relatives and accounts for 25-30% of cases, often inherited in an autosomal dominant manner.
- Genetic causes are diverse, including mutations in genes like dystrophin, actin, and lamin A/C, but molecular diagnoses are currently limited to about 10% of cases.
- A new clinical approach involves screening family members, extending evaluation to asymptomatic individuals and presenting complex genetic challenges due to heterogeneity.
Impact:
- Advances the understanding of familial DCM's genetic basis and clinical presentation.
- Highlights the need for integrated clinical and molecular genetic research to improve diagnostic capabilities.
- Underscores the critical role of interdisciplinary collaboration, potentially coordinated by scientific societies, for future progress in familial DCM.
Abstract:
The definition of familial dilated cardiomyopathy (DCM) is clinically based on the presence, in the same family, of at least two members proven as affected. The prevalence of familial forms is about 25-30%. The approach to define the prevalence of familial diseases and to identify asymptomatic subjects is based on a clinical, non-invasive screening of family members of consecutive index patients. Familial DCM is commonly inherited as autosomal dominant trait; less frequently it is autosomal recessive, X-linked or matrilinear. The disease is clinically and genetically heterogeneous. Genes causally linked to this phenotype include dystrophin, dystrophin-associated glycoproteins, actin, desmin, beta-miosin heavy chain, cardiac troponin T, and mitochondrial DNA genes, mostly transfer RNAs. A peculiar phenotype is DCM associated with atrioventricular block, an autosomal dominant disorder that is causally linked to lamin A/C gene defects in a high proportion of cases. Although the knowledge on molecular genetics of DCM is progressively increasing, at present, the number of molecular diagnoses that can be provided to patients is limited to a few X-linked, autosomal dominant and matrilinear DCMs (overall, about 10% of DCMs). The new clinical approach to familial DCM studies, based on the screening of family members, will bring to the cardiologist's attention both patients and relatives, with extension of the clinical evaluation to subjects who are still healthy. On the other hand, molecular genetists will face a complex molecular field, for both high heterogeneity and poor phenotypical specificity. Therefore, interdisciplinary clinical and research projects are especially needed, hopefully coordinated by scientific societies.