Dystrophin genotype-cardiac phenotype correlations in Duchenne and Becker muscular dystrophies using cardiac magnetic resonance imaging

Abstract

Duchenne and Becker muscular dystrophies are caused by mutations in dystrophin. Cardiac manifestations vary broadly, making prognosis difficult. Current dystrophin genotype-cardiac phenotype correlations are limited. For skeletal muscle, the reading-frame rule suggests in-frame mutations tend to yield milder phenotypes. We performed dystrophin genotype-cardiac phenotype correlations using a protein-effect model and cardiac magnetic resonance imaging. A translational model was applied to patient-specific deletion, indel, and nonsense mutations to predict exons and protein domains present within truncated dystrophin protein. Patients were dichotomized into predicted present and predicted absent groups for exons and protein domains of interest. Development of myocardial fibrosis (represented by late gadolinium enhancement [LGE]) and depressed left ventricular ejection fraction (LVEF) were compared. Patients (n = 274) with predicted present cysteine-rich domain (CRD), C-terminal domain (CTD), and both the N-terminal actin-binding and cysteine-rich domains (ABD1 + CRD) had a decreased risk of LGE and trended toward greater freedom from LGE. Patients with predicted present CTD (exactly the same as those with in-frame mutations) and ABD1 + CRD trended toward decreased risk of and greater freedom from depressed LVEF. In conclusion, genotypes previously implicated in altering the dystrophinopathic cardiac phenotype were not significantly related to LGE and depressed LVEF. Patients with predicted present CRD, CTD/in-frame mutations, and ABD1 + CRD trended toward milder cardiac phenotypes, suggesting that the reading-frame rule may be applicable to the cardiac phenotype. Genotype-phenotype correlations may help predict the cardiac phenotype for dystrophinopathic patients and guide future therapies.

Figure 1

Graphical representation of predicted present base pairs. The base pairs predicted present for each patient based on mutation data are represented with a horizontal black bar, aligned with the base pair number on the horizontal axis. Exon and protein domain boundaries are marked with a colored background. A patient was predicted to have an exon or protein domain present if all the base pairs that code for that region of interest were predicted to be present.

Figure 2

(A) Freedom from LGE and CRD intact. Kaplan–Meier freedom from LGE for patients with CRD predicted intact (n = 34) versus predicted disrupted. 25% time-to-event 14.3 versus 13.0 years; log-rank p = 0.060. (B) Freedom from LGE and CTD intact. Kaplan–Meier freedom from LGE for patients with CTD predicted intact (n = 30) versus predicted disrupted. Patients predicted to have the CTD domain intact were exactly those with in-frame deletions. 25% time-to-event 13.6 versus 13.0 years; log-rank p = 0.054. (C) Freedom from LGE and ABD1 + CRD intact. Kaplan–Meier freedom from LGE for patients with both ABD1 + CRD predicted intact (n = 21) versus those predicted to have at least 1 disrupted. Log-rank p = 0.025.

Figure 3

(A) Freedom from depressed LVEF and CTD intact. Kaplan–Meier freedom from depressed LVEF (<55%) for patients with CTD predicted intact (n = 30) versus predicted disrupted. Patients predicted to have the CTD domain intact were exactly those with in-frame deletions. Log-rank p = 0.090. (B) Freedom from depressed LVEF and ABD1 + CRD intact. Kaplan–Meier freedom from depressed LVEF (<55%) for patients with both ABD1 + CRD predicted intact (n = 21) versus those predicted to have at least 1 disrupted. Log-rank p = 0.132.