Distribution of mutations associated with congenital myasthenic syndromes (CMS): results from the first 54 specimens tested at a clinical reference laboratory
Sat Dev Batish1, Lebron Lebron1, Marc A Meservey1, Jeff S Radcliff1, Zhenyuan Wang1, Vivekananda Datta1
1Athena Diagnostics
To evaluate the frequency of mutations associated with CMS in specimens submitted for testing at a clinical reference laboratory.

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.

Among 54 patients tested, results were positive for deleterious variant(s) in 12 (22%, including 1 carrier) and negative in 26 (48%); 16 (30%) patients had variants of uncertain significance (VUS). Of the patients with deleterious variants, 7 were female and 5 were male; ages ranged from 3 to 53 years. Deleterious variants were most commonly found in CHRNE (n=6). Deleterious variants were also found in DOK7 (n=2), COLQ (n=1), MUSK (n=1), RAPSN (n=1), and GFPT1 (n=1 carrier). No deleterious variants or VUS were found in CHRNA1

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.