LIMB GIRDLE MUSCULAR DYSTROPHIES: P.145 Prevalence of CAPN3 mutations in Limb-girdle muscular dystrophy type 2A: From a multi-center analysis in China to a worldwide perspective

Abstract

Limb-girdle muscular dystrophy type 2A (LGMD2A) is a rare autosomal recessive limb-girdle muscular dystrophy caused by mutations in CAPN3 gene. To date, no systemic evaluation was performed to investigate the mutational distribution and the hot spot regions. We retrospectively reviewed CAPN3 gene mutations from 124 Chinese patients recruited from four diagnostic centers (2012 January to 2019 September). Then we integrated the multicenter analysis with open-source databases (Clinvar, LOVD, gnomAD) and annotated the combined dataset (Ref: NM_000070.3). Functional evaluating tools (SIFT, PolyPhen, dbscSNV and MaxEntScan) were used to analyze the pathogenicity of the mutations. We evaluated the frequency and distribution of allelic CAPN3 mutation in LGMD2A patients. In the allelic mutational dataset from Chinese cohort (n=112), 62 novel mutations (55.4%) were identified according to ClinVar. The most prevalent mutation in China was c.2120A>G (18.9%) while the previous reported hotspot in LOVD was c.550del. Functional analysis with Polyphen and dbscSNV revealed a higher deleterious effect in Chinese cohort in comparison to the reported data (PolyPhen: g= 0.52, p < 0.0001; dbscSNV: g=0.49, p = 0.0036). After integrating the Chinese data with reported alleles (n= 467 in total), mutations in exon 1 (8.9%) and exon 10 (8.0%) of CAPN3 had the highest frequencies, while missense and frameshift mutations accounted for the majority of mutations. CAPN3 mutations had a high frequency in Exon 1 and 10 among LGMD2A patients. Exon 1 encodes the muscle-specific NS region of Calpain-3 protein while Exon 10 corresponds to Protease Core subdomain 2 (PC2). The frequent mutational regions revealed in the LGMD2A patients.