DMD – BIOMARKERS & OUTCOME MEASURES: P.127 Identification of biallelic DMD variants during maternal carrier testing for Becker muscular dystrophy

Abstract

Dystrophinopathies are allelic X-linked recessive muscular dystrophies caused by pathogenic variants in the dystrophin (DMD) gene. In males, out-of-frame DMD variants typically cause more severe Duchenne muscular dystrophy (DMD), while in-frame variants typically result in Becker muscular dystrophy (BMD). Females who carry a DMD variant are at increased risk for cardiomyopathy and may have skeletal muscle symptoms. We report a mother (proband) and three sons, the oldest (10-year-old) and youngest (8-year-old) of whom have a pathogenic in-frame deletion of exons 45-47 and diagnoses of Becker muscular dystrophy. Both have progressive muscle weakness, recurrent rhabdomyolysis, and elevated creatine phosphokinase (CPK) levels ranging from 2,500 – 18,000 unit/L (ref 22-250 unit/L). During confirmatory carrier testing, the mother was found to carry the familial exon 45-47 deletion in addition to an unexpected second pathogenic in-frame DMD deletion of exons 49-51, which was not present in her two previously tested sons. She reports muscle cramps and pain but no muscle weakness. Cardiac MRI shows no current evidence of cardiomyopathy. DMD testing for the family's 9-year-old son detected the exon 49-51 deletion, which supported a diagnosis of BMD for him and confirmed the two DMD changes are situated on opposite alleles in his mother. He had an existing diagnosis of Perthes disease, but had otherwise not come to clinical attention for BMD-related symptoms. The family had reported that CPK levels measured locally had been within normal limits. CPK levels measured subsequent to genetic testing were mildly elevated (up to 321 unit/L), and muscle pain and fatigue were noted during clinical visit, consistent with BMD. This case highlights unexpected outcomes of maternal dystrophinopathy carrier testing, namely the detection of a second variant not previously known in the family, and subsequent diagnosis of BMD in a son who had been presumed to be unaffected. These results underscore the importance of genetic counselling in this setting. This case also describes an additional example of mild BMD in the setting of exon 49-51 deletion, as well as a further example of biallelic DMD variants in a female, of which only a few cases have been described.