PDF(Pubmed)
Abstract：
Objective: Nemaline myopathies are a heterogeneous group of congenital myopathies caused by mutations in different genes associated with the structural and functional proteins of thin muscular filaments. Most patients have congenital onset characterized by hypotonia, respiratory issues, and abnormal deep tendon reflexes, which is a phenotype encountered in a wide spectrum of neuromuscular disorders. Whole-exome sequencing (WES) contributes to a faster diagnosis and facilitates genetic counseling. Methods: Here, we report on two Arab patients from consanguineous families diagnosed with nemaline myopathy of different phenotype spectrum severities. Results: Clinical assessment and particular prenatal history raised suspicion of neuromuscular disease. WES identified homozygous variants in NEB and KLHL40. Muscle biopsy and muscle magnetic resonance imaging studies linked the genetic testing results to the clinical phenotype. The novel variant in the NEB gene resulted in a classical type 2 nemaline myopathy, while the KLHL40 gene variant led to a severe phenotype of nemaline myopathy, type 8. Both patients were identified as having other gene variants with uncertain roles in their complex phenotypes. Conclusions: This study enriches the phenotypic spectrum of nemaline myopathy caused by NEB and KLHL40 variants and highlights the importance of detailed prenatal, neonatal, and infancy assessments of muscular weakness associated with complex systemic features. Variants of uncertain significance in genes associated with nemaline myopathy may be correlated with the phenotype. Early, multidisciplinary intervention can improve the outcome in patients with mild forms of nemaline myopathies. WES is essential for clarifying complex clinical phenotypes encountered in patients from consanguineous families. Targeted carrier screening of extended family members would enable accurate genetic counseling and potential genetic prevention.
摘要：
目的：神经肌病是一组异质性的先天性肌病，由与肌肉细丝的结构和功能蛋白相关的不同基因突变引起。大多数患者具有以张力过低为特征的先天性发作，呼吸问题,和异常的深肌腱反射，这是在广泛的神经肌肉疾病中遇到的表型。全外显子组测序（WES）有助于更快的诊断并促进遗传咨询。方法:这里,我们报道了两名来自近亲家庭的阿拉伯患者，他们被诊断患有不同表型谱严重程度的线虫性肌病。结果：临床评估和特定的产前病史引起了对神经肌肉疾病的怀疑。WES鉴定了NEB和KLHL40中的纯合变体。肌肉活检和肌肉磁共振成像研究将基因检测结果与临床表型联系起来。NEB基因中的新变体导致经典的2型线虫肌病，而KLHL40基因变异导致了严重的线虫肌病表型，类型8.两名患者均被鉴定为具有在其复杂表型中具有不确定作用的其他基因变体。结论：本研究丰富了由NEB和KLHL40变异引起的线虫性肌病的表型谱，并强调了详细产前，新生儿,以及与复杂系统特征相关的肌肉无力的婴儿期评估。与线虫性肌病相关的基因中意义不确定的变异可能与表型相关。早期，多学科干预可以改善轻度形式的线虫肌病患者的预后。WES对于澄清近亲家庭患者遇到的复杂临床表型至关重要。对大家庭成员进行有针对性的携带者筛查将能够进行准确的遗传咨询和潜在的遗传预防。
