Molecular landscape of DYSF mutations in dysferlinopathy: From a Chinese multicenter analysis to a worldwide perspective

Dysferlinopathy is one of the most common subgroup of autosomal recessive limb-girdle muscular dystrophies that is caused by mutations in DYSF gene. However, there is currently no worldwide comprehensive genetic analysis of DYSF variants. Through a national multicenter collaborative effort in China, we identified 222 DYSF variants with 40 novel variants from 245 patients. We then integrated DYSF variants from disease-related genetic databases including LOVD (n = 1020) and Clinvar (n = 1179), to depict the global landscape of disease-related DYSF variants. Normal-population-derived DSYF variants from gnomAD (n = 4318) and ChinaMAP (n = 13,330) were also analyzed in comparison. In Chinese patients, gender instead of genotype showed influence on the onset age of dysferlinopathy, with males showing an earlier age of onset. After integrative analysis, we identified two hotspot DYSF mutations, c.2997G>T in world patients and c.1375dup in Chinese patients, respectively. Both the pathogenic and likely pathogenic variants scattered on the whole gene length of DYSF. However, three specific domains (C2F-C2G-TM, DysF, and C2B-Ferl-C2C) contained variants at higher frequencies than reported in both the databases and Chinese patients. This study comprehensively collected available DYSF variant data, which may pave way for genetic counselling and future clinical trial design for gene therapies in dysferlinopathy.