PDF(Pubmed)
Abstract：
BACKGROUND: Using the Clinical Audit Research and Evaluation of Motor Neuron Disease (CARE-MND) database and the Scottish Regenerative Neurology Tissue Bank, we aimed to outline the genetic epidemiology and phenotypes of an incident cohort of people with MND (pwMND) to gain a realistic impression of the genetic landscape and genotype-phenotype associations.
METHODS: Phenotypic markers were identified from the CARE-MND platform. Sequence analysis of 48 genes was undertaken. Variants were classified using a structured evidence-based approach. Samples were also tested for C9orf72 hexanucleotide expansions using repeat-prime PCR methodology.
RESULTS: 339 pwMND donated a DNA sample: 44 (13.0%) fulfilled criteria for having a pathogenic variant/repeat expansion, 53.5% of those with a family history of MND and 9.3% of those without. The majority (30 (8.8%)) had a pathogenic C9orf72 repeat expansion, including two with intermediate expansions. Having a C9orf72 expansion was associated with a significantly lower Edinburgh Cognitive and Behavioural ALS Screen ALS-Specific score (p = 0.0005). The known pathogenic SOD1 variant p.(Ile114Thr), frequently observed in the Scottish population, was detected in 9 (2.7%) of total cases but in 17.9% of familial cases. Rare variants were detected in FUS and NEK1. One individual carried both a C9orf72 expansion and SOD1 variant.
CONCLUSIONS: Our results provide an accurate summary of MND demographics and genetic epidemiology. We recommend early genetic testing of people with cognitive impairment to ensure that C9orf72 carriers are given the best opportunity for informed treatment planning. Scotland is enriched for the SOD1 p.(Ile114Thr) variant and this has significant implications with regards to future genetically-targeted treatments.
METHODS: Phenotypic markers were identified from the CARE-MND platform. Sequence analysis of 48 genes was undertaken. Variants were classified using a structured evidence-based approach. Samples were also tested for C9orf72 hexanucleotide expansions using repeat-prime PCR methodology.
RESULTS: 339 pwMND donated a DNA sample: 44 (13.0%) fulfilled criteria for having a pathogenic variant/repeat expansion, 53.5% of those with a family history of MND and 9.3% of those without. The majority (30 (8.8%)) had a pathogenic C9orf72 repeat expansion, including two with intermediate expansions. Having a C9orf72 expansion was associated with a significantly lower Edinburgh Cognitive and Behavioural ALS Screen ALS-Specific score (p = 0.0005). The known pathogenic SOD1 variant p.(Ile114Thr), frequently observed in the Scottish population, was detected in 9 (2.7%) of total cases but in 17.9% of familial cases. Rare variants were detected in FUS and NEK1. One individual carried both a C9orf72 expansion and SOD1 variant.
CONCLUSIONS: Our results provide an accurate summary of MND demographics and genetic epidemiology. We recommend early genetic testing of people with cognitive impairment to ensure that C9orf72 carriers are given the best opportunity for informed treatment planning. Scotland is enriched for the SOD1 p.(Ile114Thr) variant and this has significant implications with regards to future genetically-targeted treatments.
摘要：
背景：使用运动神经元疾病的临床审核研究和评估（CARE-MND）数据库和苏格兰再生神经病学组织库，我们旨在概述MND患者(pwMND)事件队列的遗传流行病学和表型,以获得对遗传格局和基因型-表型关联的真实印象.
方法:从CARE-MND平台鉴定表型标记。对48个基因进行序列分析。使用结构化的基于证据的方法对变体进行分类。还使用重复初免PCR方法测试样品的C9orf72六核苷酸扩增。
结果：339pwMND捐赠了DNA样本：44（13.0％）符合致病性变异/重复扩增的标准，有MND家族史的人中有53.5％，没有MND家族史的人中有9.3％。大多数(30例(8.8%))有致病性C9orf72重复扩增，包括两个中间扩张。C9orf72扩展与爱丁堡认知和行为ALS屏幕ALS特异性得分显着降低相关（p=0.0005）。已知的致病性SOD1变体p。（Ile114Thr），经常在苏格兰人口中观察到，在9例（2.7％）的总病例中检测到，但在17.9％的家族病例中检测到。在FUS和NEK1中检测到罕见变异。一个个体携带C9orf72扩增和SOD1变体。
结论：我们的结果提供了MND人口统计学和遗传流行病学的准确总结。我们建议对认知障碍患者进行早期基因检测，以确保C9orf72携带者获得知情治疗计划的最佳机会。苏格兰富含SOD1p。（Ile114Thr）变体，这对未来的遗传靶向治疗具有重要意义。
方法:从CARE-MND平台鉴定表型标记。对48个基因进行序列分析。使用结构化的基于证据的方法对变体进行分类。还使用重复初免PCR方法测试样品的C9orf72六核苷酸扩增。
结果：339pwMND捐赠了DNA样本：44（13.0％）符合致病性变异/重复扩增的标准，有MND家族史的人中有53.5％，没有MND家族史的人中有9.3％。大多数(30例(8.8%))有致病性C9orf72重复扩增，包括两个中间扩张。C9orf72扩展与爱丁堡认知和行为ALS屏幕ALS特异性得分显着降低相关（p=0.0005）。已知的致病性SOD1变体p。（Ile114Thr），经常在苏格兰人口中观察到，在9例（2.7％）的总病例中检测到，但在17.9％的家族病例中检测到。在FUS和NEK1中检测到罕见变异。一个个体携带C9orf72扩增和SOD1变体。
结论：我们的结果提供了MND人口统计学和遗传流行病学的准确总结。我们建议对认知障碍患者进行早期基因检测，以确保C9orf72携带者获得知情治疗计划的最佳机会。苏格兰富含SOD1p。（Ile114Thr）变体，这对未来的遗传靶向治疗具有重要意义。
