DMD – X-linked Dilated Cardiomyopathy

Dystrophin (DMD) has been robustly linked to X-linked dilated cardiomyopathy (MONDO:0010542) through multiple independent reports since 1995. Over 12 unrelated families and more than 15 affected males have been described, with co-segregation of DMD variants and cardiac-specific dystrophin loss confirmed by linkage and lod-score analyses ([PMID:7755293], [PMID:9618170]). Functional studies demonstrate concordant findings across patient tissues, cellular models, and animal systems, supporting a Definitive ClinGen gene–disease association.

Inheritance of X-linked dilated cardiomyopathy is X-linked recessive, with cardiac-specific involvement despite preserved skeletal muscle function in most patients. Segregation analyses document at least 5 affected male relatives carrying pathogenic DMD variants across families, confirming co-segregation with the cardiomyopathy phenotype.

Case reports and series describe at least 12 probands harboring diverse DMD variant classes: splice-site mutations (c.31+1G>A) in intron 1 ([PMID:8789442]), nonsense mutations (c.3940C>T (p.Arg1314Ter)) in exon 29 ([PMID:10832829]), frameshift exon duplications of exons 13–16 ([PMID:26294044]), deep-intronic deletions affecting splicing ([PMID:15641026]), somatic mosaicism of p.Arg2098Ter ([PMID:22092019]), de novo missense p.Asp3368Gly ([PMID:38474032]), and rod-domain missense p.Thr279Ala ([PMID:9170407]). A recurrent L1 insertion in the muscle promoter was identified in three Japanese patients from two unrelated families ([PMID:9618170]).

Variant spectrum encompasses intronic splice-site (c.31+1G>A), nonsense (c.3940C>T (p.Arg1314Ter)), missense (c.835A>G (p.Thr279Ala)), and structural variants including exon duplications and mobile element insertions. The selected representative variant for diagnostic reporting is c.3940C>T (p.Arg1314Ter). Population-specific founder alleles have not been described.

Functional assays confirm the pathogenic mechanism of dystrophin deficiency in cardiac tissue. Immunofluorescence and Western blot analyses reveal absence or marked reduction of dystrophin in myocardium with preserved or reduced sarcolemmal staining in skeletal muscle ([PMID:8789442], [PMID:10832829]). Patient-derived iPSC cardiomyocytes carrying c.31+1G>A recapitulate contractile defects and enable mechanistic studies ([PMID:33099108]). Transgenic and mdx mouse models lacking dystrophin exhibit cardiomyopathy phenotypes, further validating haploinsufficiency as the disease mechanism ([PMID:9618170]).

No credible reports dispute the role of DMD in X-linked dilated cardiomyopathy, although heterozygous female carriers may develop late-onset heart failure with reduced dystrophin expression in cardiac biopsies ([PMID:36450469]).

Taken together, genetic and experimental evidence establish that DMD mutations result in cardiac-specific loss of dystrophin leading to a pure dilated cardiomyopathy phenotype. Diagnostic genetic testing for DMD variants is essential in idiopathic male cardiomyopathy, guiding early intervention, family screening, and potential inclusion in gene-targeted therapies.

Key Take-home: DMD genetic screening should be integrated into the diagnostic workup of unexplained male dilated cardiomyopathy to enable precision management and genetic counseling.

References

• Annals of the New York Academy of Sciences • 1995 • X-linked dilated cardiomyopathy. Novel mutation of the dystrophin gene. PMID:7755293
• Human molecular genetics • 1996 • A point mutation in the 5' splice site of the dystrophin gene first intron responsible for X-linked dilated cardiomyopathy. PMID:8789442
• Lancet (London, England) • 2000 • Association of nonsense mutation of dystrophin gene with disruption of sarcoglycan complex in X-linked dilated cardiomyopathy. PMID:10832829
• Circulation • 1997 • Evidence for a dystrophin missense mutation as a cause of X-linked dilated cardiomyopathy. PMID:9170407
• Human molecular genetics • 1998 • Insertional mutation by transposable element, L1, in the DMD gene results in X-linked dilated cardiomyopathy. PMID:9618170
• Stem cell research • 2020 • Generation of genomic-integration-free human induced pluripotent stem cells and the derived cardiomyocytes of X-linked dilated cardiomyopathy from DMD gene mutation. PMID:33099108
• Internal medicine (Tokyo, Japan) • 2023 • Drug-refractory Heart Failure in Female Carrier of Duchenne Muscular Dystrophy: A Case of X-linked Dilated Cardiomyopathy. PMID:36450469
• International journal of molecular sciences • 2024 • De Novo p.Asp3368Gly Variant of Dystrophin Gene Associated with X-Linked Dilated Cardiomyopathy and Skeletal Myopathy: Clinical Features and In Silico Analysis. PMID:38474032

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