背景:由编码外周髓磷脂蛋白22(PMP22)的基因重复引起,Charcot-Marie-Tooth病1A型(CMT1A)是最常见的遗传性神经病。尽管有这种共同的遗传起源,临床严重程度存在相当大的差异。假设遗传修饰因子有助于这种异质性,对其进行鉴定可能会揭示新的治疗靶标。在这项研究中,我们对来自RDCRN-INC(遗传性神经病变联盟)进行的前瞻性自然史研究的1564例CMT1A患者的临床检查结果进行了综合分析.我们的主要目标是描绘该患者队列中的极端表型特征(轻度和重度)。从而增强我们检测具有大效应的遗传修饰因子的能力。
方法:我们对RDCRN-INC数据库进行了大规模统计分析,以表征多个指标的CMT1A严重性。
结果:我们根据CMT检查评分V2和足背屈力(MRC量表)定义了年龄标准化疾病严重程度的第10(轻度)和第90(重度)百分位以下的患者。基于极端表型类别,我们定义了一个统计上合理的招聘策略,我们建议在未来的修饰符研究中使用。
结论:利用碱基对分辨率的全基因组测序,未来的遗传修饰评估将包括单核苷酸关联,基因负荷测试,和结构变异分析。目前的工作不仅提供了对CMT1A的严重性和过程的洞察,但也阐明了我们打算对全球招募的额外患者实施的具有成本效益和直接的患者招募策略的统计学基础和实际考虑因素.
BACKGROUND: Caused by duplications of the gene encoding peripheral myelin protein 22 (PMP22), Charcot-Marie-Tooth disease type 1A (CMT1A) is the most common hereditary neuropathy. Despite this shared genetic origin, there is considerable variability in clinical severity. It is hypothesized that genetic modifiers contribute to this heterogeneity, the identification of which may reveal novel therapeutic targets. In this
study, we present a comprehensive analysis of clinical examination results from 1564 CMT1A patients sourced from a prospective natural history
study conducted by the RDCRN-INC (Inherited Neuropathy Consortium). Our primary objective is to delineate extreme phenotype profiles (mild and severe) within this patient cohort, thereby enhancing our ability to detect genetic modifiers with large effects.
METHODS: We have conducted large-scale statistical analyses of the RDCRN-INC database to characterize CMT1A severity across multiple metrics.
RESULTS: We defined patients below the 10th (mild) and above the 90th (severe) percentiles of age-normalized disease severity based on the CMT Examination Score V2 and foot dorsiflexion strength (MRC scale). Based on extreme phenotype categories, we defined a statistically justified recruitment strategy, which we propose to use in future modifier studies.
CONCLUSIONS: Leveraging whole genome sequencing with base pair resolution, a future genetic modifier evaluation will include single nucleotide association, gene burden tests, and structural variant analysis. The present work not only provides insight into the severity and course of CMT1A, but also elucidates the statistical foundation and practical considerations for a cost-efficient and straightforward patient enrollment strategy that we intend to conduct on additional patients recruited globally.