Familial Dilated Cardiomyopathy

Anant Khositseth, MD; Virginia V. Michels, MD


Cardiovasc Rev Rep. 2004;25(5) 

In This Article

Molecular Genetic Basis of Familial DCM

Familial DCM can be categorized by inheritance pattern and clinical phenotype. For purposes of this review, DCM that is usually associated with skeletal myopathies or other organ system disease will not be discussed further. Nearly two thirds of familial DCM involves autosomal-dominant inheritance.[7] Penetrance is incomplete and age-related; in one study, penetrance was 10% at age <20 years, 34% at age 20-30 years, 60% at age 30-40 years, and 90% at age >40 years.[7] However, there is a wide range of age of onset within and between families, from infancy to older adulthood.[3] Molecular genetic studies using linkage analysis and/or the candidate gene approach have identified eight genes associated with autosomal-dominant DCM:[8] TPM1 (chromosome 15q22.1, encoding α-tropomyosin),[9] ACTC (chromosome 15q11-qter, encoding cardiac actin),[10] DES (chromosome 2q35, encoding desmin),[8] TTN (chromosome 2q24.3-q31, encoding titin),[11] SGCD (chromosome 5q33, encoding δ sarcoglycan),[12] MYH7 (chromosome 14q11.2, encoding β-myosin heavy chain),[13] TNNT2 (chromosome 1q32, encoding cardiac troponin T) and VCL (chromosome 10q22.1-q23, encoding metavinculin).[14] Other chromosomal loci have been identified for which the genes remain unknown. At least seven (with two recognized genes, LMN4 and EYA4) loci for autosomal-dominant DCM associated with other cardiac abnormalities, such as prominent conduction defects, sinus node dysfunction, mitral valve prolapse, and/or with skeletal muscle or other organ involvement, have also been identified.[8]

Autosomal-recessive DCM seems to be less frequent and may be characterized by a significantly younger age of onset and a worse prognosis compared with the dominant form. Some may be associated with the limb-girdle muscular dystrophies caused by mutations in the genes coding for sarcoglycans; however, autosomal-recessive DCM without other organ involvement also may exist due to mutations in these or other genes.[8,15,16]

X-linked familial DCM can be due to dystrophin gene (DYS) mutations on chromosome Xp21.3.[7,17] Although dystrophin mutations usually cause Duchenne or Becker muscular dystrophies,[18] dystrophin mutations also can cause isolated DCM.[7] The gene TAZ (chromosome Xq28, encoding tafazzin) is associated with DCM, which can be lethal in infancy or compatible with adult-onset noncompaction DCM. Mutations in the tafazzin gene also can cause Barth syndrome characterized by DCM plus skeletal myopathy, neutropenia, and 3-methyl glutaconic aciduria.[18,19] EMD (chromosome Xq28, encoding emerin) can cause DCM with progressive conduction system disease, with or without skeletal myopathy, particularly in female carriers.[20]


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