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.

中文翻译：

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在112名伊朗患者队列中，常染色体隐性隐性腰带型肌营养不良症的突变谱，并报道了可能的创始人效应。

背景技术腰带型肌营养不良症是一组遗传性异质性疾病，以常染色体显性遗传（LGMDD）和常染色体隐性遗传（LGMDR）遗传，后者尤其常见于近亲血缘高的婚姻人群，例如伊朗。在本研究中，我们旨在调查可疑受LGMDR影响的患者的遗传基础。从他们的全血中提取了60个怀疑有LGMD的家庭的DNA样本。为与LGMD R1（钙蛋白酶3相关）-R6（δ-糖聚糖相关）相关的每个候选基因选择四个短串联重复（STR）标记，并将所有这24个STR应用于两组多重PCR中。在自动合子作图之后，进行了Sanger测序和变体分析。预测识别出的变体的效果是使用计算机内工具进行的，根据美国医学基因组学和遗传学学会（ACMG）指南对它们进行了解释。MLPA用于那些缺失较大的患者。新鲜的肌肉标本取自受试者，并使用常规的组织化学染色剂进行评估。结果60个家庭中的40个在CAPN3，DYSF，SGCA和SGCB基因中显示了纯合子单倍型。对相关基因的外显子和内含子-外显子边界进行测序，共鉴定出38个突变，包括CAPN3（n = 15），DYSF（n = 9），SGCB（n = 11）和SGCA（n = 3）。其中五个是新颖的。在我们的研究中，最常见的LGMD形式是钙蛋白酶病，其次是肌糖蛋白病，其中β-肌糖蛋白病是其中最常见的形式。SGCB基因中外显子2缺失是这项研究中最常见的突变。我们还报告了在DYSF和SGCB基因突变的家庭中可能存在创始人效应的证据。我们还检测到一个患有钙蛋白酶病的大近亲家庭，这些家庭表现出等位基因异质性。结论这项研究可以扩大我们对伊朗LGMD遗传谱的了解，并暗示在某些伊朗亚人群中可能存在的创始人效应，以更多的样本量证实这一点可以促进我们的遗传诊断和遗传咨询。