Journal article
A study concept of expeditious clinical enrollment for genetic modifier studies in Charcot-Marie-Tooth neuropathy 1A
Journal of the peripheral nervous system, Vol.29(2), pp.202-212
04/05/2024
DOI: 10.1111/jns.12621
PMCID: PMC11209807
PMID: 38581130
Abstract
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.
We have conducted large-scale statistical analyses of the RDCRN-INC database to characterize CMT1A severity across multiple metrics.
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.
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.
Details
- Title: Subtitle
- A study concept of expeditious clinical enrollment for genetic modifier studies in Charcot-Marie-Tooth neuropathy 1A
- Creators
- Isaac R L Xu - University of MiamiMatt C Danzi - University of MiamiAriel Ruiz - Dr. John T. Macdonald FoundationJacquelyn Raposo - Dr. John T. Macdonald FoundationYeisha Arcia De Jesus - Dr. John T. Macdonald FoundationMary M Reilly - National Hospital for Neurology and NeurosurgeryAndrea Cortese - National Hospital for Neurology and NeurosurgeryMichael E Shy - University of IowaSteven S Scherer - University of PennsylvaniaDavid N Herrmann - University of Rochester Medical CenterVera Fridman - University of Colorado Anschutz Medical CampusJonathan Baets - University of AntwerpMario Saporta - University of MiamiReza Seyedsadjadi - Harvard Medical SchoolTanya Stojkovic - Pitié-Salpêtrière HospitalKristl G Claeys - KU LeuvenPooja Patel - University of PennsylvaniaShawna Feely - University of IowaAdriana P Rebelo - University of MiamiMaike F Dohrn - RWTH Aachen UniversityStephan Züchner - University of MiamiInherited Neuropathy Consortium
- Resource Type
- Journal article
- Publication Details
- Journal of the peripheral nervous system, Vol.29(2), pp.202-212
- DOI
- 10.1111/jns.12621
- PMID
- 38581130
- PMCID
- PMC11209807
- NLM abbreviation
- J Peripher Nerv Syst
- eISSN
- 1529-8027
- Grant note
- NIH HHS
- Language
- English
- Electronic publication date
- 04/05/2024
- Academic Unit
- Neurology; Molecular Physiology and Biophysics; Iowa Neuroscience Institute
- Record Identifier
- 9984584905102771
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