A novel mutation of dystrophin in a Becker muscular dystrophy family with severe cardiac involvement: from genetics to clinicopathology

Abstract

Background: Dystrophin gene defects are the pathogenic molecular basis of Becker muscular dystrophy (BMD), characterised by skeletal myopathy and cardiomyopathy. Because of the broad phenotype spectrum, it was difficult to use the traditional diagnostic method to achieve an early accurate diagnosis of BMD-associated cardiomyopathy.

Methods: We applied an in-house gene panel testing and a gene-filtering strategy to investigate the genetic defect in a four-generation family with 73 members. The proband had a heart transplant due to heart failure; the explanted heart was subjected to a careful pathological analysis.

Results: A novel small in-frame mutation (c.4998_5000 del CAG, p.1667 del Ala) of the dystrophin gene was identified and co-segregated in the affected family members. By using the image segmentation technology, we found the left ventricular free wall demonstrated severe fibrofatty replacement of cardiac myocytes from the epicardium to the endocardium.

Conclusion: We identified a novel dystrophin mutation (p.1667 del Ala), resulting in BMD-associated cardiomyopathy that demonstrated the pathological features of significant fibrofatty replacement in the sub-epicardial layer of the ventricle; further, the high-throughput sequencing is helpful for making an early diagnosis of BMD.

Keywords: BMD; Cardiomyopathy; Dystrophin; Fibrofatty replacement.