背景:先天性肌强直症(MC)是一种罕见的疾病,分为两种主要形式;由CLCN1基因突变引起的汤姆森和贝克尔病,影响肌肉兴奋性并编码电压门控氯通道(CLC-1)。同时,没有关于埃及患者肌强直的临床和分子特征的数据.
方法:这里,我们报告了来自六个无关家庭的7名埃及MC患者。在临床诊断之后,全外显子组测序(WES)用于基因诊断.各种计算机预测工具被用来解释变异致病性。然后使用Sanger测序技术验证候选变体。
结果:总计,招募了七个案例。检查年龄从8个月到19岁不等。临床表现包括热身现象,手柄,和打击乐肌强直。所有患者均进行了肌电图检查,并显示肌强直放电。分子遗传分析揭示了五种不同的变异。其中,我们鉴定了CLCN1基因中的两个新变体(c.1583G>C;p.Gly528Ala和c.2203_2216del;p。Thr735ValfsTer57)和CLCN1和SCN4A基因中的三个已知变体。根据虚拟工具,预测鉴定的新变体具有有害作用。
结论:作为第一个在埃及MC患者中应用WES的研究,我们的研究结果报道了两个新的杂合变体,它们扩展了用于MC诊断的CLCN1突变谱.这些结果进一步证实,基因检测对于早期诊断MC至关重要。影响临床实践中的后续治疗和预后评估。
BACKGROUND: Myotonia Congenita (MC) is a rare disease classified into two major forms; Thomsen and Becker disease caused by mutations in the CLCN1 gene, which affects muscle excitability and encodes voltage-gated chloride channels (CLC-1). While, there are no data regarding the clinical and molecular characterization of myotonia in Egyptian patients.
METHODS: Herein, we report seven Egyptian MC patients from six unrelated families. Following the clinical diagnosis, whole-exome sequencing (WES) was performed for genetic diagnosis. Various in silico prediction tools were utilized to interpret variant pathogenicity. The candidate variants were then validated using Sanger sequencing technique.
RESULTS: In total, seven cases were recruited. The ages at the examination were ranged from eight months to nineteen years. Clinical manifestations included warm-up phenomenon, hand grip, and percussion myotonia. Electromyography was performed in all patients and revealed myotonic discharges. Molecular genetic analysis revealed five different variants. Of them, we identified two novel variants in the CLCN1 gene ( c.1583G > C; p.Gly528Ala and c.2203_2216del;p.Thr735ValfsTer57) and three known variants in the CLCN1 and SCN4A gene. According to in silico tools, the identified novel variants were predicted to have deleterious effects.
CONCLUSIONS: As the first study to apply WES among Egyptian MC patients, our findings reported two novel heterozygous variants that expand the CLCN1 mutational spectrum for MC diagnosis. These results further confirm that genetic testing is essential for early diagnosis of MC, which affects follow-up treatment and prognostic assessment in clinical practice.