- Title
- DMD-associated dilated cardiomyopathy : genotypes, phenotypes, and phenocopies
- Creator
- Johnson, Renee; Otway, Robyn; Chin, Ephrem; Horvat, Claire; Ohanian, Monique; Wilcox, Jon; Su, Zheng; Prestes, Priscilla; Smolnikov, Andrei; Soka, Magdalena; Guo, Guanglan; Rath, Emma; Chakravorty, Samya; Chrzanowski, Lukasz; Hayward, Christopher; Keogh, Anne; MacDonald, Peter; Giannoulatou, Eleni; Chang, Alex; Oates, Emily; Charchar, Fadi; Seidman, Jonathan; Seidman, Christine; Hegde, Madhuri; Fatkin, Diane
- Date
- 2023
- Type
- Text; Journal article
- Identifier
- http://researchonline.federation.edu.au/vital/access/HandleResolver/1959.17/198455
- Identifier
- vital:19065
- Identifier
-
https://doi.org/10.1161/CIRCGEN.123.004221
- Identifier
- ISSN:2574-8300 (ISSN)
- Abstract
- 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. © 2023 American Heart Association, Inc.
- Publisher
- Lippincott Williams and Wilkins
- Relation
- Circulation: Genomic and Precision Medicine Vol. 16, no. 5 (2023), p. 421-430
- Rights
- All metadata describing materials held in, or linked to, the repository is freely available under a CC0 licence
- Rights
- https://creativecommons.org/licenses/by-nc-nd/4.0
- Rights
- Copyright © 2023 American Heart Association, Inc.
- Rights
- Open Access
- Subject
- 3201 Cardiovascular medicine and haematology; Dilated cardiomyopathy; Dystrophin; Genetics; Heart; Titin
- Full Text
- Reviewed
- Funder
- This work was supported by grants from the National Health and Medical Research Council of Australia (1123472: Dr Charchar; 1074386; Dr Fatkin), NSW Health (Dr Fatkin), Shanghai Pujiang Program (19PJ1407000; Dr Chang); The Program for Professor of Special Appointment (Eastern Scholar) at Shanghai Institutions of Higher Learning (0900000024; Dr Chang); Innovative Research Team of High-Level Local Universities in Shanghai (SHSMU-ZLCX20211700; Dr Chang); the American Heart Association (13POST14480004, 18CDA34110411; Dr Chang), National Heart, Lung, and Blood Institute or the National Institutes of Health (1R01HL080494,1R01HL084553; C.E. Seidman and J.G. Seidman), Howard Hughes Medical Institute (C.E. Seidman).
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