Congenital LAMA2 related muscular dystrophy (LAMA2-RD), the most commonly recognized type of congenital muscular dystrophies, has been described in patients' cohorts from Europe and the UK but not from Middle-Eastern. This study aimed to reveal the prevalence, clinical and genomic characteristics of congenital LAMA2-RD in a patient's cohort of 17 families (21 patients) from the Gulf and Middle East. Affected subjects exhibited the classic phenotype of generalized hypotonia, developmental delay, and progressive muscular weakness. Despite the homogeneous background of most of our patients, clinical variability was evident; however, none of our patients was able to achieve independent ambulation. The associated features of nephrocalcinosis, infantile-onset osteopenia, and cardiac arrest were first described in this study. LAMA2 mutations constituted 48% of the genetic causes underlying congenital muscular dystrophies (CMDs) in our patients. We estimated a point prevalence of 0.8 in 100.000 for LAMA2-RD in Qatar, relatively higher compared to that described in Europe's studies. The founder mutation and high rate of consanguinity are potential contributors. This study identified five LAMA2 truncating variants, two novel and three recurrent, of which the c.6488delA-frameshift that was found in 12 unrelated Qatari families, highlighting a founder mutation in Qatari patients. The two novel variants involved an acceptor splice site and N-terminus deletion that removes the LAMA2 promoter, exon1, and part of intron1. The "residual" expression of LAMA2 transcript and protein associated with this large N-terminus deletion suggested an alternative promoter that, while seems to be activated, acts less efficiently.

中文翻译：

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来自卡塔尔的一组患者中 LAMA2 相关先天性肌营养不良症的临床和基因组特征。特定人群的创始人变体

先天性 LAMA2 相关肌营养不良症 (LAMA2-RD) 是最常见的先天性肌营养不良症类型，已在来自欧洲和英国的患者队列中有所描述，但未在中东地区进行描述。本研究旨在揭示来自海湾和中东的 17 个家庭（21 名患者）的患者队列中先天性 LAMA2-RD 的患病率、临床和基因组特征。受影响的受试者表现出全身性张力减退、发育迟缓和进行性肌肉无力的典型表型。尽管我们大多数患者的背景均一，但临床变异性很明显。然而，我们的患者中没有一个能够实现独立行走。本研究首次描述了肾钙质沉着症、婴儿期骨质减少和心脏骤停的相关特征。LAMA2 突变占我们患者先天性肌营养不良症 (CMD) 潜在遗传原因的 48%。我们估计卡塔尔 LAMA2-RD 的患病率为 0.8/100.000，与欧洲研究中描述的相比相对较高。创始人突变和高血缘率是潜在的贡献者。该研究确定了五个 LAMA2 截短变异，两个新的和三个复发的，其中在 12 个不相关的卡塔尔家庭中发现了 c.6488delA 移码，突出了卡塔尔患者的创始人突变。这两个新变体涉及一个受体剪接位点和 N 端删除，删除 LAMA2 启动子、外显子 1 和内含子 1 的一部分。LAMA2 转录本和与这种大 N 端缺失相关的蛋白质的“残留”表达表明了一个替代启动子，