Advantages of clinical exome sequencing as a second step in genetic screening of patients with suspected Duchenne/Becker muscular dystrophy

Among myodystrophies that debut in early childhood and require early diagnosis and treatment, progressive Duchenne/Becker muscular dystrophy (DMD/BMD, OMIM: 310200) remains the most common and severe form in male patients. The most promising method of modern diagnostics as the second stage of genetic screening of patients with suspected DMD/BMD is clinical exome sequencing. This approach makes it possible to identify pathogenic and likely pathogenic variants not only in the DMD gene, but also in genes associated with other forms of neuromuscular diseases.

The aim of this study was to evaluate the use of clinical exome sequencing as the second stage of genetic screening of patients with suspected progressive Duchenne/Becker muscular dystrophy or other forms of NMD in the Northwestern region of the Russian Federation. The main inclusion criteria were: a previously established clinical diagnosis of DMD/BMD, as well as a significant increase in the level of creatine phosphokinase (creatine kinase, CPK) (>1000U/L), transaminases (according to age-referenced values) – alanine aminotransferase (ALT) and aspartate aminotransferase (AST). In the first stage of the study, patients with a presumptive diagnosis of DMD/BMD were tested for the presence of extended deletions and duplications in the DMD gene using the multiplex ligase chain reaction method. In a second step, patients in whom deletions and duplications were not detected were sequenced for the “clinical” exome by NGS, which includes 3332 genes. A total of 167 patients were examined, with a mean age of 7±2 years. Pathogenic and likely pathogenic variants in the DMD gene, as well as in genes associated with other forms of inherited neuromuscular diseases described previously in RF patients, were identified in 114 patients (68.3%) in our cohort. In 11 patients (6.6%), variants in genes that are not included in the existing RF noncommercial NGS panels for the diagnosis of DMD/BMD and other types of muscular dystrophies were detected, which emphasizes the importance of exome sequencing in patients with a presumptive diagnosis of DMD/BMD for differential diagnosis.

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