CMS is a group of conditions identified by muscle weakness that worsens with physical exertion. These conditions have variable age of onset, symptoms, and severity. Because treatments that improve one type of CMS may exacerbate another, genetic diagnosis is important, but is not widely available.

We evaluated the distribution of CMS-associated mutations among deidentified clinical specimens submitted for testing at Athena Diagnostics. Variants in the following genes were assessed using targeted advanced hybrid capture (next-generation) sequencing of genomic DNA: AGRN, CHAT, CHRNA1, CHRNB1, CHRND, CHRNE, COLQ, DOK7, DPAGT1, GFPT1, MUSK, RAPSN, SCN4A. Target regions included coding regions and ≥10 adjacent non-coding nucleotides. Validation testing demonstrated 99% sensitivity and specificity for detecting DNA sequence variations.

This sequencing panel detected variants associated with CMS in 22% of patients tested, including 1 carrier. The most commonly affected gene was CHRNE, followed by DOK7. VUS were also observed. As we gain more insight into CMS, the clinical significance of these VUS in this rare disorder may be recognized.