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

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 -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.

De Novo p.Asp3368Gly Variant of Dystrophin Gene Associated with X-Linked Dilated Cardiomyopathy and Skeletal Myopathy: Clinical Features and In Silico Analysis

“…XLDCM was first described by Berko and Swift in 1987 as a rapidly progressive form of DCM [ 12 ]. XLDCM is an extremely rare and distinct phenotype of dystrophinopathy (<3%) characterized by preferential cardiac involvement without any overt skeletal myopathy [ 13 ]. Patients with isolated XLDCM may have complete dystrophin loss in cardiac muscle.…”

Molecular and Biochemical Therapeutic Strategies for Duchenne Muscular Dystrophy

“…BMD, characterized by later-onset muscle weakness, sees heart failure as the main cause of morbidity and mortality, with the average age of death in the mid-40s. DMD-associated DCM is marked by congestive cardiac failure and left ventricular dilatation [ 2 ]. Mutations in the DMD gene ( Figure 1 ) cause DMD.…”

Novel Insights Into DMD-Associated Dilated Cardiomyopathy

“…In this issue of Circulation: Genomic and Precision Medicine , Johnson et al 6 evaluate the spectrum of genetic variation in DMD -associated DCM from a cohort of 174 subjects with suspected heritable cardiomyopathies. Within this study cohort, they selected 40 male probands (39/40 with European ancestry) with DCM and family history suggestive of X-linked inheritance and performed both conventional (panel sequencing) and structural (multiplex polymerase chain reaction, array comparative genomic hybridization) genetic testing on all 40 subjects.…”