DMD-Associated Dilated Cardiomyopathy: Genotypes, Phenotypes, and Phenocopies

Johnson, Renee and Otway, Robyn and Chin, Ephrem and Horvat, Claire and Ohanian, Monique and Wilcox, Jon A.L. and Su, Zheng and Prestes, Priscilla and Smolnikov, Andrei and Soka, Magdalena and Guo, Guanglan and Rath, Emma and Chakravorty, Samya and Chrzanowski, Lukasz and Hayward, Christopher S. and Keogh, Anne M. and Macdonald, Peter S. and Giannoulatou, Eleni and Chang, Alex C.Y. and Oates, Emily C. and Charchar, Fadi and Seidman, Jonathan G. and Seidman, Christine E. and Hegde, Madhuri and Fatkin, Diane (2023) DMD-Associated Dilated Cardiomyopathy: Genotypes, Phenotypes, and Phenocopies. Circulation: Genomic and Precision Medicine, 16 (5). pp.421-430. ISSN 2574-8300

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BACKGROUND: Variants in the DMD gene, that encodes the cytoskeletal protein, dystrophin, cause a severe form of dilated cardiomyopathy (DCM) associated with high rates of heart failure, heart transplantation, and ventricular arrhythmias. Improved early detection of individuals at risk is needed. METHODS: Genetic testing of 40 male probands with a potential X-linked genetic cause of primary DCM was undertaken using multi-gene panel sequencing, multiplex polymerase chain reaction, and array comparative genomic hybridization. Variant location was assessed with respect to dystrophin isoform patterns and exon usage. Telomere length was evaluated as a marker of myocardial dysfunction in left ventricular tissue and blood. RESULTS: Four pathogenic/likely pathogenic DMD variants were found in 5 probands (5/40: 12.5%). Only one rare variant was identified by gene panel testing with 3 additional multi-exon deletion/duplications found following targeted assays for structural variants. All of the pathogenic/likely pathogenic DMD variants involved dystrophin exons that had percent spliced-in scores >90, indicating high levels of constitutive expression in the human adult heart. Fifteen DMD variant-negative probands (15/40: 37.5%) had variants in autosomal genes including TTN, BAG3, LMNA, and RBM20. Myocardial telomere length was reduced in patients with DCM irrespective of genotype. No differences in blood telomere length were observed between genotype-positive family members with/without DCM and controls. CONCLUSIONS: Primary genetic testing using multi-gene panels has a low yield and specific assays for structural variants are required if DMD-associated cardiomyopathy is suspected. Distinguishing X-linked causes of DCM from autosomal genes that show sex differences in clinical presentation is crucial for informed family management.

Item Type: Article
Subjects: R Medicine > R Medicine (General)
Depositing User: Repository Administrator
Date Deposited: 01 May 2024 04:44
Last Modified: 01 May 2024 04:44

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