PDF(Pubmed)
Abstract：
BACKGROUND: Congenital myopathies are severe genetic diseases with a strong impact on patient autonomy and often on survival. A large number of patients do not have a genetic diagnosis, precluding genetic counseling and appropriate clinical management. Our objective was to find novel pathogenic variants and genes associated with congenital myopathies and to decrease diagnostic odysseys and dead-end.
METHODS: To identify pathogenic variants and genes implicated in congenital myopathies, we established and conducted the MYOCAPTURE project from 2009 to 2018 to perform exome sequencing in a large cohort of 310 families partially excluded for the main known genes.
RESULTS: Pathogenic variants were identified in 156 families (50%), among which 123 families (40%) had a conclusive diagnosis. Only 44 (36%) of the resolved cases were linked to a known myopathy gene with the corresponding phenotype, while 55 (44%) were linked to pathogenic variants in a known myopathy gene with atypical signs, highlighting that most genetic diagnosis could not be anticipated based on clinical-histological assessments in this cohort. An important phenotypic and genetic heterogeneity was observed for the different genes and for the different congenital myopathy subtypes, respectively. In addition, we identified 14 new myopathy genes not previously associated with muscle diseases (20% of all diagnosed cases) that we previously reported in the literature, revealing novel pathomechanisms and potential therapeutic targets.
CONCLUSIONS: Overall, this approach illustrates the importance of massive parallel gene sequencing as a comprehensive tool for establishing a molecular diagnosis for families with congenital myopathies. It also emphasizes the contribution of clinical data, histological findings on muscle biopsies, and the availability of DNA samples from additional family members to the diagnostic success rate. This study facilitated and accelerated the genetic diagnosis of congenital myopathies, improved health care for several patients, and opened novel perspectives for either repurposing of existing molecules or the development of novel treatments.
METHODS: To identify pathogenic variants and genes implicated in congenital myopathies, we established and conducted the MYOCAPTURE project from 2009 to 2018 to perform exome sequencing in a large cohort of 310 families partially excluded for the main known genes.
RESULTS: Pathogenic variants were identified in 156 families (50%), among which 123 families (40%) had a conclusive diagnosis. Only 44 (36%) of the resolved cases were linked to a known myopathy gene with the corresponding phenotype, while 55 (44%) were linked to pathogenic variants in a known myopathy gene with atypical signs, highlighting that most genetic diagnosis could not be anticipated based on clinical-histological assessments in this cohort. An important phenotypic and genetic heterogeneity was observed for the different genes and for the different congenital myopathy subtypes, respectively. In addition, we identified 14 new myopathy genes not previously associated with muscle diseases (20% of all diagnosed cases) that we previously reported in the literature, revealing novel pathomechanisms and potential therapeutic targets.
CONCLUSIONS: Overall, this approach illustrates the importance of massive parallel gene sequencing as a comprehensive tool for establishing a molecular diagnosis for families with congenital myopathies. It also emphasizes the contribution of clinical data, histological findings on muscle biopsies, and the availability of DNA samples from additional family members to the diagnostic success rate. This study facilitated and accelerated the genetic diagnosis of congenital myopathies, improved health care for several patients, and opened novel perspectives for either repurposing of existing molecules or the development of novel treatments.
摘要：
背景：先天性肌病是严重的遗传性疾病，对患者的自主性有很大影响，通常对患者的生存也有很大影响。大量患者没有基因诊断，排除遗传咨询和适当的临床管理。我们的目标是发现与先天性肌病相关的新型致病变异和基因，并减少诊断错误和死胡同。
方法：为了确定与先天性肌病有关的致病变异和基因，我们从2009年至2018年建立并实施了MYOCAPTURE项目,对310个部分排除主要已知基因的家族进行外显子组测序.
结果：在156个家族（50％）中发现了致病性变异，其中123个家庭(40%)确诊.只有44例（36％）已解决的病例与已知的具有相应表型的肌病基因有关，而55（44％）与具有非典型体征的已知肌病基因的致病变异有关，强调在该队列中，大多数基因诊断不能基于临床组织学评估来预测。对于不同的基因和不同的先天性肌病亚型，观察到了重要的表型和遗传异质性。分别。此外,我们发现了14个新的肌病基因以前与肌肉疾病相关（占所有诊断病例的20％），我们以前在文献中报道过，揭示新的病理机制和潜在的治疗靶点。
结论：总体而言，这种方法说明了大规模平行基因测序作为建立先天性肌病家族分子诊断的综合工具的重要性.它还强调了临床数据的贡献，肌肉活检的组织学发现，以及来自其他家庭成员的DNA样本的可用性，以诊断成功率。这项研究促进和加速了先天性肌病的遗传诊断，改善了几个病人的医疗保健，并为重新利用现有分子或开发新的治疗方法开辟了新的视角。
方法：为了确定与先天性肌病有关的致病变异和基因，我们从2009年至2018年建立并实施了MYOCAPTURE项目,对310个部分排除主要已知基因的家族进行外显子组测序.
结果：在156个家族（50％）中发现了致病性变异，其中123个家庭(40%)确诊.只有44例（36％）已解决的病例与已知的具有相应表型的肌病基因有关，而55（44％）与具有非典型体征的已知肌病基因的致病变异有关，强调在该队列中，大多数基因诊断不能基于临床组织学评估来预测。对于不同的基因和不同的先天性肌病亚型，观察到了重要的表型和遗传异质性。分别。此外,我们发现了14个新的肌病基因以前与肌肉疾病相关（占所有诊断病例的20％），我们以前在文献中报道过，揭示新的病理机制和潜在的治疗靶点。
结论：总体而言，这种方法说明了大规模平行基因测序作为建立先天性肌病家族分子诊断的综合工具的重要性.它还强调了临床数据的贡献，肌肉活检的组织学发现，以及来自其他家庭成员的DNA样本的可用性，以诊断成功率。这项研究促进和加速了先天性肌病的遗传诊断，改善了几个病人的医疗保健，并为重新利用现有分子或开发新的治疗方法开辟了新的视角。
