Key result
Genetic analysis of 112 Iranian patients with suspected limb-girdle muscular dystrophy identified 38 mutations across 40 families, revealing calpainopathy as the most prevalent subtype and 5 novel mutations.
Why the study?
Autosomal recessive limb-girdle muscular dystrophies are common in populations with high consanguineous marriages, prompting investigation of the genetic basis in Iranian patients suspected of LGMDR.
Observational (n=112)
Calpainopathy is the most prevalent form of autosomal recessive limb-girdle muscular dystrophy in this Iranian cohort, with evidence of a possible founder effect.
May inform targeted LGMD panels in Iranian consanguineous families; leaves open broader applicability pending larger validation.
BACKGROUND: Limb-girdle muscular dystrophies are a group of genetically heterogeneous diseases that are inherited in both autosomal dominant (LGMDD) and autosomal recessive forms (LGMDR), the latter is more common especially in populations with high consanguineous marriages like Iran. In the present study, we aimed to investigate the genetic basis of patients who are suspicious of being affected by LGMDR. DNA samples of 60 families suspected of LGMD were extracted from their whole blood. Four short tandem repeat (STR) markers for each candidate genes related to LGMD R1 (calpain3 related)- R6 (δ-sarcoglycan-related) were selected, and all these 24 STRs were applied in two sets of multiplex PCR. After autozygosity mapping, Sanger sequencing and variant analysis were done. Predicting identified variants' effect was performed using in-silico tools, and they were interpreted according to the American College of Medical Genomics and Genetics (ACMG) guideline. MLPA was used for those patients who had large deletions. Fresh muscle specimens were taken from subjects and were evaluated using the conventional panel of histochemical stains. RESULTS: forty out of sixty families showed homozygote haplotypes in CAPN3, DYSF, SGCA, and SGCB genes. The exons and intron-exon boundaries of the relevant genes were sequenced and totally 38 mutations including CAPN3 (n = 15), DYSF (n = 9), SGCB (n = 11), and SGCA (n = 3) were identified. Five out of them were novel. The most prevalent form of LGMDs in our study was calpainopathy followed by sarcoglycanopathy in which beta-sarcoglycanopathy was the most common form amongst them. Exon 2 deletion in the SGCB gene was the most frequent mutation in this study. We also reported evidence of a possible founder effect in families with mutations in DYSF and SGCB genes. We also detected a large consanguineous family suffered from calpainopathy who showed allelic heterogeneity. CONCLUSIONS: This study can expand our knowledge about the genetic spectrum of LGMD in Iran, and also suggest the probable founder effects in some Iranian subpopulations which confirming it with more sample size can facilitate our genetic diagnosis and genetic counseling.
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Mojbafan et al. (2020) conducted an observational in Autosomal recessive limb-girdle muscular dystrophies (n=112). Genetic mutations (CAPN3, DYSF, SGCA, SGCB) was evaluated on Detection of disease-causing mutations in CAPN3, DYSF, SGCA, and SGCB genes. Genetic analysis of 112 Iranian patients with suspected limb-girdle muscular dystrophy identified 38 mutations across 40 families, revealing calpainopathy as the most prevalent subtype and 5 novel mutations.
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