Muscular dystrophies (MDs) are a heterogeneous group of inherited disorders that are characterized by progressive skeletal muscle weakness and dystrophic changes on muscle biopsy. The broad genetic and clinical heterogeneity of MDs make the accurate diagnosis difficult via conventional approaches. This study investigated 23 patients from eight unrelated consanguineous families with MDs. Previous clinical assessments did not accurately clarify the type of their MD and/or misdiagnose them with another disease. Exome sequencing (ES) is an efficient, time-saving, and cost-effective tool, enabling disease-causing variant (DCV) detection in affected individuals. We investigated the use of ES to diagnose MD and discover the underlying genetic etiology. We achieved a remarkable diagnostic success rate of 87.5% (7 out of 8 families) which is the highest rate reported thus far compared to previous studies. We identified two novel pathogenic variants in DYSF gene (c.4179delG, c.1149+3G > C). The latter variant impacts the splicing machinery of DYSF mRNA. Moreover, we further assessed the pathogenicity of four recurrent variants ((DYSF, c.4076T > C), (GMPPB, c.458C > T), (SGCA, c.739G > A) (TTN, c.7331G > A), designated their neurological impact and added new phenotypes in patients with these variants. To our knowledge, this is the first study applying an ES-based comprehensive molecular diagnosis to Jordanian cohort with MDs. Our findings confirmed that ES is a powerful approach for the diagnosis of MD patients. This efficient method of molecular diagnosis is crucial for guiding patient clinical care, genetic counseling, and most importantly, paving the way for gene therapy which is currently in clinical trials.

肌营养不良（MDs）是遗传疾病的异质性组，其特征是进行性骨骼肌无力和肌肉活检的营养不良变化。MD的广泛遗传和临床异质性使得通过常规方法难以进行准确的诊断。这项研究调查了来自8个无关的近亲家族的23例MD。先前的临床评估未能准确阐明其MD的类型和/或将其误诊为另一种疾病。外显子组测序（ES）是一种高效，省时且具有成本效益的工具，可在受影响的个体中检测出致病变异（DCV）。我们调查了使用ES诊断MD并发现潜在的遗传病因。我们的诊断成功率高达87。5％（8个家庭中的7个）是迄今为止报道的最高比率。我们确定了两个新的致病变异DYSF基因（c.4179delG，c.1149 + 3G> C）。后一种变体影响DYSF mRNA的剪接机制。此外，我们进一步评估了四个复发性变体（（DYSF，c.4076T> C），（GMPPB，c.458C> T），（SGCA，c.739G> A）（TTN，c.7331G> A），指定了它们的神经学影响并在具有这些变异的患者中添加了新的表型。据我们所知，这是第一项将基于ES的综合分子诊断应用于MD的约旦人队列的研究。我们的发现证实，ES是诊断MD患者的有效方法。这种有效的分子诊断方法对指导患者的临床护理，遗传咨询至关重要，最重要的是，为目前在临床试验中的基因治疗铺平了道路。