Xu, Isaac RL;
Danzi, Matt C;
Ruiz, Ariel;
Raposo, Jacquelyn;
De Jesus, Yeisha Arcia;
Reilly, Mary M;
Cortese, Andrea;
... Zuchner, Stephan; + view all
(2024)
A study concept of expeditious clinical enrollment for genetic modifier studies in Charcot-Marie-Tooth neuropathy 1A.
Journal of the Peripheral Nervous System
, 29
(2)
pp. 202-212.
10.1111/jns.12621.
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Abstract
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. Interpretation: 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.
| Type: | Article |
|---|---|
| Title: | A study concept of expeditious clinical enrollment for genetic modifier studies in Charcot-Marie-Tooth neuropathy 1A |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1111/jns.12621 |
| Publisher version: | https://doi.org/10.1111/jns.12621 |
| Language: | English |
| Additional information: | This version is the author accepted manuscript. For information on re-use, please refer to the publisher’s terms and conditions. |
| Keywords: | ASSOCIATION, BURDEN, Charcot-Marie-Tooth disease, CHILDREN, Clinical Neurology, CMT NEUROPATHY, CMT1A, CMTES, DISEASE, disease severity, DUPLICATION, genetic modifiers, Life Sciences & Biomedicine, MOTOR, natural history, NATURAL-HISTORY, Neurosciences, Neurosciences & Neurology, phenotype outliers, PMP22, Science & Technology, TYPE-1, whole genome sequencing |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Brain Sciences > UCL Queen Square Institute of Neurology > Department of Neuromuscular Diseases |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10213413 |
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