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Familial dilated cardiomyopathy

Clinical and genetic characteristics

Familäre dilatative Kardiomyopathie

Klinische und genetische Faktoren

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Abstract

Familial dilated cardiomyopathy (F-DCM) describes a clinically and genetically heterogeneous group of diseases, mostly inherited as autosomal dominant traits, having idiopathic left ventricular dilatation and dysfunction as a common phenotype. The age of onset, rate of progression, disease complications, as well as overall prognosis and outcome vary both amongst and within families. Clinical traits, both cardiac and extracardiac, may recur in association with the DCM phenotype. The former include conduction defects, structural abnormalities such as left ventricular noncompaction, of right ventricular involvement, and recurrence of atrial or ventricular arrhythmias; the latter commonly affect the musculoskeletal (myopathies/dystrophies, both clinically overt and subclinical), ocular, auditory, nervous, and integument systems. These traits may help guide genetic testing. In parallel to the clinical heterogeneity, F-DCM also shows genetic heterogeneity: more than 40 genes have been causally linked to F-DCM, with mutations recurring more commonly in a few known genes, and less frequently in rare, less commonly known genes. Based on the known prevalence of mutations in disease genes, more than 50% of F-DCM cases can be regarded as still genetically orphan, implying that further disease genes have to be discovered. Family screening and genetic testing are now established as the gold standard for diagnosis, care, and prevention in F-DCM. Diagnostic tests are performed using Sanger-based sequencing. Furthermore, new biotechnology tools, based on next-generation sequencing, are now being implemented in the research setting and will dramatically modify the future of the nosology of F-DCM.

Zusammenfassung

Mit der Diagnose einer familären dilatativen Kardiomyopathie (F-DCM) wird eine klinisch und genetisch heterogene Gruppe von Erkrankungen beschrieben, die als Genotyp einen autosomal-dominanten Vererbungsgang mit dem Phänotyp einer linksventrikulären Dilatation und Dysfunktion verbindet. Variabel sind der Beginn, die Progressionsgeschwindigkeit, die Komplikationen und die Prognose der Erkrankungen im Vergleich einzelner Betroffener und innerhalb der Familien. Kardiale und extrakardiale klinische Charakteristika können sich parallel zum Phänotyp der kardialen Dilatation entwickeln, dazu gehören aber auch Reizleitungsstörungen, strukturelle Veränderungen wie die linksventrikuläre „non compaction“, die Beteiligung der rechten Ventrikels sowie atriale und ventrikuläre Arrhythmien. Extrakardiale Charakteristika betreffen meist die Skelettmuskulatur mit dem klinischen Erscheinungsbild einer Myopathie oder Dystrophie, Seh- und Hörstörungen sowie Beeinträchigungen des Nervensystems und eine Hautbeteiligung. Diese Charakteristika können für die genetischen Untersuchungen oft entscheidenden Hinweischarakter haben.

Neben der klinischen weist die F-DMC auch eine genetische Heterogenität auf: Mehr als 40 Gene kodieren für die F-DCM, wobei Mutationen häufig in nur wenigen, bekannten Genen und weniger oft in den seltenen, weniger bekannten Krankheitsgenen auftreten. Unter Berücksichtigung der bekannten Prävalenz von Mutationen in Krankheitsgenen dürften bei mehr als 50% der F-DCM-Patienten weitere Krankheitsgene entdeckt werden.

Familienscreening und genetische Kaskadenuntersuchungen sind heute die am besten geeigneten Instrumente für Diagnosestellung, Behandlung und Prävention bei familiärer DCM. Diagnostische Tests basieren zum einen auf der Sanger-Sequenzanalyse, zum anderen sind neue biotechnologische Techniken auf der Grundlage des „next generation sequencing“ bereits heute Teil der Forschung und werden die Nosologie der familären DCM drastisch verändern.

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Acknowledgments

Supported by EU Project No. 291924 INHERITANCE.

Conflict of interest

On behalf of all authors, the corresponding author states that there are no conflicts of interest.

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Authors and Affiliations

  1. Centre for Inherited Cardiovascular Diseases, I.R.C.C.S. Foundation San Matteo Hospital, Piazzale Golgi 19, 27100, Pavia, Italy

    A. Serio, N. Narula, T. Kodama, V. Favalli & E. Arbustini

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  1. A. Serio
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  2. N. Narula
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  3. T. Kodama
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  4. V. Favalli
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  5. E. Arbustini
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Correspondence to E. Arbustini.

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Serio, A., Narula, N., Kodama, T. et al. Familial dilated cardiomyopathy. Herz 37, 822–829 (2012). https://doi.org/10.1007/s00059-012-3707-9

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