Identification of Biallelic dystrophin gene variants during maternal carrier testing for Becker muscular dystrophy and review of the DMD exon 49–51 deletion phenotype

Background Dystrophinopathies are X‐linked recessive conditions caused by pathogenic variants in the dystrophin (DMD) gene. In a family that included two boys with Becker muscular dystrophy (BMD) due to a DMD deletion of exons 45–47, maternal carrier testing unexpectedly identified biallelic DMD deletions of exons 45–47 and 49–51. Methods The patient's mild phenotype in the setting of biallelic DMD variants prompted further investigation of the exon 49–51 deletion in particular, via literature review and retrospective chart review of patients who have been evaluated in our institution's comprehensive neuromuscular center and/or diagnosed in our clinical genetic testing laboratory. Results To our knowledge, this is only the fifth case of confirmed biallelic DMD variants in a female. In males, the DMD exon 49–51 deletion appears to result in a mild BMD phenotype with low or normal creatine kinase levels. This deletion comprised 19% (4/21) of dystrophinopathies diagnosed by chromosomal microarray (CMA) in males during the past ten years in our clinical laboratory. Most individuals identified by chart review were diagnosed through CMA, despite the fact that microarray was genome‐wide and not DMD‐specific. This case raised important genetic counseling issues. Conclusion The DMD exon 49–51 deletion appears to cause a variable but generally mild BMD phenotype. Its relatively frequent detection by CMA suggests it may be underdiagnosed. This manuscript summarizes a case of biallelic dystrophin (DMD) variants in a mildly affected female patient and additionally highlights the phenotypic spectrum of one of the patient's two DMD variants, a deletion of exons 49–51. This deletion previously had few reports in the published literature, despite its frequency within our institution's neuromuscular clinic. We identified 15 additional cases of this deletion through our retrospective chart review, adding considerable knowledge to the 27 cases we initially located through a literature search.