Congenital myasthenic syndrome (CMS) encompasses a heterogeneous group of inherited disorders affecting nerve transmission across the neuromuscular junction. 1 The incidence of CMS was estimated to be 1.8-22.2 per million; however, due to the complexity of the procedures that are used to obtain an accurate diagnosis, incidence rates are likely underestimated. [2][3][4][5][6] Currently, more than 30 proteins are known to be involved in various types of CMS. Generally, proteins related to CMS are located at the presynaptic, synaptic or postsynaptic region of the neuromuscular junction (NMJ), or they undergo abnormal glycosylation. Among them, mutations in CHRNE, RAPSN and COLQ are the most frequent, accounting for half of CMS cases in a large-scale analysis including 680 patients. 7 Mutations in CMS-related genes can be used to accurately diagnose CMS.Generally, CMS is characterized by fatigability or skeletal muscle weakness with an onset at birth to early childhood.Electromyographic findings of a decrease in repetitive nerve stimulation (RNS) and increased jitter on single-fibre electromyography (EMG) may support the diagnosis. 8 Genetic testing or whole-exome sequencing could establish a diagnosis of CMS and guide pharmacological treatment. For example, β2-receptor agonist therapy could

Calsequestrin 1 (CASQ1) is the most crucial Ca 2+ binding protein localized in the sarcoplasmic reticulum (SR) of skeletal muscle. With high capacity and low affinity for Ca 2+ , CASQ1 plays a significant role in maintaining a large amount of Ca 2+ necessary for muscle contraction. However, only five mutations in CASQ1 have been identified to date. Here, we report a 42‐year‐old Chinese female patient who presented with a 12 years history of slowly progressive upper limb weakness, predominantly affecting distal muscles, which was uncommon comparing to other CASQ1‐related patients. Next‐generation sequencing (NGS) analysis revealed a novel heterozygous mutation (c.766G > A, p.Val256Met) in CASQ1 . Functional studies confirmed the likely pathogenicity of this variant. Muscle histopathology revealed rare optically empty vacuoles in myofibers and atypical eosinophilic granules in the cytoplasm, which has not been observed before. We also performed a literature review on all the pathogenic mutations in CASQ1 and summarized their genetic and clinical characteristics. This is the first report on CASQ1‐related myopathy from China, further expanding the mutation spectrum of CASQ1 gene and provides new insights into the function of CASQ1.