Identification of Compound Heterozygous Variants in OBSCN Gene Associated With Rhabdomyolysis: A Case Report.

Background: The obscurin protein encoded by the OBSCN gene is an important structural protein in the regulation of myocyte sarcoplasmic nodule stability and sarcoplasmic reticulum function and is particularly closely associated with calcium ion (Ca²⁺) signaling. With increasing genomic studies, pathogenic variants in the OBSCN gene have been shown to be associated with a variety of inherited diseases, such as cardiomyopathy. However, case reports of its variants causing rhabdomyolysis are more limited.

Methods: We performed whole exome sequencing on a patient with exercise-induced rhabdomyolysis to identify possible causative gene variants. In addition, functional prediction of the pathogenicity of the variants was performed by combining multiple bioinformatics analysis tools and in-depth analyses with clinical phenotypes and family history.

Results: The patient carried compound heterozygous variants, including c.21184C>T (nonsense variant) and c.15610+12C>T (intronic splicing variant). The c.21184C>T variant resulted in a premature termination of the protein, was not included in population-based databases, and was supported by multiple prediction tools as a potentially pathogenic variant. The c.15610+12C>T variant was also absent in the gnomAD_EAS database and predicted to disturb normal splicing, potentially creating a novel donor site. The pathogenicity of the variant is further supported by the fact that the patient's mother, with a homozygous OBSCN variant, also exhibited exercise-induced myalgia. Clinically, the patient presented with exercise-induced rhabdomyolysis accompanied by significant serum creatine kinase elevation, muscle pain, and MRI-demonstrated muscle edema of both lower limbs without significant muscle weakness or cardiac abnormalities.

Conclusion: We report the first case of rhabdomyolysis in China caused by OBSCN gene variants. This finding further extends the spectrum of the OBSCN gene variants. It also provides an important basis for genetic counseling and helps in the early diagnosis and management of similar cases.