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

Abstract

Background: The dysferlin gene or the DYSF gene encodes the Ca 2+-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 dystrophy involving progressive muscle weakness and atrophy. The present study aimed to identify the variants responsible for the clinical symptoms of a Chinese patient with limb girdle muscular dystrophies (LGMDs) and to explore the genotypephenotype associations of LGMD2B. Methods: A series of clinical examinations, including blood tests, magnetic resonance imaging scans for the lower legs, electromyography and muscle biopsy, was performed on the proband diagnosed with muscular dystrophies. Whole exome sequencing was conducted to detect the causative variants, followed by Sanger sequencing to validate these variants. Results: We identified two compound heterozygous variants in the DYSF gene, c.1058 T>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 (Polymorphism Phenotyping v2; http://genetics.bwh.harvard.edu/pph2), SIFT (Sorting Intolerant From Tolerant; https://sift.bii.a-star.edu.sg), PROVEAN (Protein Variation Effect Analyzer; http://provean.jcvi.org/seq_submit.php) and MutationTaster (http://www. mutationtaster.org). In addition, the two compound heterozygous variants in the proband were absent in 100 control individuals who had an identical ethnic origin and were from the same region, suggesting that 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 the pathogenesis of LGMDs and accelerates the development of a prenatal diagnosis.

Clinical, Neurophysiological, Radiological, Pathological, and Genetic Features of Dysferlinopathy in Saudi Arabia

“…Compound heterozygous DYSF gene mutations leading to dysferlinopathy had been reported in the literature (Nguyen et al, 2007;Li et al, 2017;Liu et al, 2018). Compound heterozygosity refers to the presence of two or more heterogeneous recessive alleles at a particular locus capable of causing genetic disease in a heterozygous state.…”

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

“…LGMD2B mainly affects the proximal lower extremity muscle tissue in the youth; As the disease progresses, the scapular girdle and upper extremity muscles may also be affected, but the symptoms are mild; the ear, neck, and hand muscles are generally spared (21). MM is an adult-onset disorder characterized by early-onset gastrocnemius weakness, which is also accompanied by an increase in serum CK concentration (22). But the onset of MM was found to be earlier than that of LGMD2B in the Italian population (23).…”

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

“…MM is an adult-onset disorder characterized by early-onset gastrocnemius weakness, which is also accompanied by an increase in serum CK concentration [ 23 ]. But the onset of MM was found to be earlier than that of LGMD R2 in the Italian population [ 24 ]. Other phenotypes associated with dysferlin deficiency have also been identified, including distal anterior myopathy (DACM) (also known as distal tibial onset distal myopathy), and proximal-distal phenotype (PD) (this phenotype may be a proximally rapidly progressive MM) [ 25 , 26 ] and asymptomatic hyperCKemia.…”

“…The top three outcomes in the world patients dataset were missense (42.3%), splicing (13.7%), and frameshift (11.1%) [19]. Chinese patients showed a similar pattern of variant sequence distribution as patients worldwide [17][18][19][20][21][22][23][24][25]39] (Table 2). Most reported pathogenic variants for dysferlinopathy are single nucleotide variants and small insert/deletions [37], but large exonic deletions and duplications have also been described [38].…”