Compound heterozygous DYSF variants causing limb-girdle muscular dystrophy type 2B in a Chinese family.

BACKGROUND The dysferlin gene or the DYSF gene encodes a Ca2+ dependent phospholipid-binding protein dysferlin which belongs to the ferlin family and is associated with muscle membrane regeneration and repair. Variants in the DYSF gene are responsible for limb-girdle muscular dystrophy type 2B (LGMD2B), also called limb-girdle muscular dystrophy recessive 2 (LGMDR2), a rare subtype of muscular dystrophies with progressive muscle weakness and atrophy. The present study aims to identify the variants responsible for the clinical symptoms of a Chinese patient with limb girdle muscular dystrophies (LGMDs) and to explore the genotype-phenotype associations of LGMD2B. METHODS A series of clinical examinations including blood tests, magnetic resonance imaging (MRI) scans for the lower legs, electromyography (EMG) and muscle biopsy were performed on the proband diagnosed with muscular dystrophies. Whole exome sequencing (WES) was conducted to detect the causative variants, followed by Sanger sequencing to validate these variants subsequently. RESULTS We identified two compound heterozygous variants in the DYSF gene c.1058T>C, p.(Leu353Pro) in exon 12 and c.1461C>A/p.Cys487* in exon 16 in this proband, which were inherited from the father and mother, respectively. In-silico analysis for these variants revealed deleterious results by PolyPhen-2, SIFT, PROVEAN and MutationTaster. In addition, the two compound heterozygous variants in the proband were absent in 100 control individuals with identical ethnic origin from the same region, suggesting these variants may be the pathogenic variants responsible for the LGMD2B phenotypes for this proband. CONCLUSIONS The present study broadens our understanding of the mutational spectrum of the DYSF gene, which provides a deep insight into further study in LGMDs pathogenesis and accelerates the development of prenatal diagnosis.