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

Abstract

Dysferlinopathy is one of the most common subgroup of autosomal recessive limbgirdle 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. Normalpopulation-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.

The clinical, myopathological, and molecular characteristics of 26 Chinese patients with dysferlinopathy: a high proportion of misdiagnosis and novel variants

“…In this study, we reviewed the clinical and molecular characteristics of 26 Chinese patients with dysferlinopathy screened by immunohistochemistry and genetic analysis, and identified a high proportion of novel variants which expand the genetic spectrum of dysferlinopathy. Recently Zhong et al reported 245 dysferlinopathy patients in 2021, although, our data further supplemented their study [11] and emphasized the importance of differentiation from inflammatory myopathy.…”

“…The screening of DYSF variants was conducted as described previously [11,19] (transcript number NM_003494.4). Most of the clinical exome sequencing analysis were accomplished by MyGenosticsInc, Beijing, China.…”

“…Immunohistochemistry (IHC) showed highly reduced expression of dysferlin protein, which is still a mandatory criterion for a positive diagnosis [ 15 ]. But since similar manifestations can also be seen in some other secondary myopathies, gene diagnosis remains the gold standard [ 16 ]. In this study, we reviewed the clinical and molecular characteristics of 26 Chinese patients with dysferlinopathy screened by immunohistochemistry and genetic analysis, and identified a high proportion of novel variants which expand the genetic spectrum of dysferlinopathy.…”

“…LGMD R2 is the second most common form of LGMD in Western countries [9] and Japan [10] and is the most prevalent genotype of LGMD in China [11].…”

Clinical heterogeneity and molecular characteristics in a group of Chinese patients with dysferlinopathy

“…A wide range of DYSF mutations has been identi ed, including missense, nonsense, frameshift deletions/insertions, splice mutations, and large exonic deletions (9). The top three outcomes in the world patients dataset were missense (42.3%), splicing (13.7%), and frameshift (11.1%) (17). Missense mutations accounted for nearly half of the study in this cohort, and a comparison of the mutational spectrum with a large French cohort (37) suggested a possible difference, with null mutations being lower in the Chinese cohort (25% vs 76%), while missense mutations were more common in the Chinese cohort (43% vs 24%).…”