Characterization of Novel Splicing Mutations and a Recurrent Deletion in COLQ Congenital Myasthenic Syndrome

Congenital myasthenic syndromes (CMS) represent a heterogeneous group of inherited disorders resulting from mutations in genes that encode proteins essential for neuromuscular transmission. Among these, mutations in the collagen-like tail subunit of asymmetric acetylcholinesterase (COLQ) define a distinct subtype of CMS, necessitating specialized diagnostic and therapeutic strategies to improve patient outcomes. Herein, we analyzed five COLQ-CMS patients, focusing on their clinical features, electrophysiologic findings, genetic characteristics, and therapeutic responses. All five patients exhibited limb-girdle weakness, and two experienced acute respiratory insufficiency. The age of symptom onset ranged from 2 to 33 years, with an average diagnostic delay of 14 years. All patients exhibited a decremental response to repetitive nerve stimulation and myopathic features on electromyography. Using whole exome sequencing (WES), complemented by PCR-based screening and reverse transcription-PCR (RT-PCR) to clarify deletion and splicing mutations, five variants of the COLQ gene were identified. These included two novel splicing mutations, c.393 + 3A>G and c.814_814 + 2dup, which caused aberrant splicing and premature truncation. Additionally, we found the deletion of exon 14–15 of the COLQ gene in three patients. All patients received salbutamol, leading to significant alleviation of primary symptoms during treatment. In conclusion, our findings offer critical insights into the clinical diagnosis and management of COLQ-CMS and highlight the importance of recognizing clinical heterogeneity, diagnostic delays, and early genetic diagnosis, which may ultimately assist clinicians in accurately identifying and effectively treating such conditions.