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Neurogenetics
Original research
Next-generation sequencing in Charcot-Marie-Tooth: a proposal for improvement of ACMG guidelines for variant evaluation
  1. Alessandro Geroldi1,
  2. Alessia Mammi1,2,
  3. Andrea Gaudio2,
  4. Serena Patrone1,
  5. Andrea La Barbera2,
  6. Paola Origone1,2,
  7. Clarissa Ponti1,2,
  8. Francesca Sanguineri1,2,
  9. Sara Massucco1,3,
  10. Lucio Marinelli1,3,
  11. Marina Grandis1,3,
  12. Angelo Schenone1,3,
  13. Paola Mandich1,2,
  14. Emilia Bellone1,2,
  15. Fabio Gotta2
  1. 1 Department of Neurosciences, Rehabilitation, Ophthalmology, Genetic and Maternal and Infantile Sciences, University of Genoa, Genova, Italy
  2. 2 UOC Medical Genetics, IRCCS Ospedale Policlinico San Martino, Genova, Italy
  3. 3 UOC Neurology Clinic, IRCCS Ospedale Policlinico San Martino, Genova, Italy
  1. Correspondence to Emilia Bellone, Department of Neurosciences, Rehabilitation, Ophthalmology, Genetic and Maternal and Infantile Sciences, University of Genoa, Genova, Italy; ebellone{at}unige.it

Abstract

Background The application of massive parallel sequencing technologies in the molecular analysis of Charcot-Marie-Tooth (CMT) has enabled the rapid and cost-effective identification of numerous potentially significant variants for diagnostic purposes. The objective is to reduce the number of variants, focusing only on those with pathogenic significance. The 2015 American College of Medical Genetics and Genomics (ACMG) guidelines aid in achieving this goal, but it is now evident that a pathology or gene-specific review of these rules is essential to avoid misinterpretations that may result from blindly applying the criteria. This study demonstrates how revised ACMG criteria, combined with CMT-specific literature data and expertise, can alter the final classification of a variant.

Methods We reviewed ACMG criteria based on current knowledge of CMT and provided suggestions for adapting them to the specificities of CMT.

Results Of the 226 index patients analysed, a diagnostic yield of 20% was obtained. It is worth noting that the 9% of cases had their final diagnosis changed with the application of the revised criteria, often resulting in the loss of the pathogenic classification of a variant.

Conclusions The widespread availability of high-throughput sequencing technologies has enabled genetic testing even for laboratories without specific disease expertise. Disease-specific ACMG criteria can be a valuable tool to prevent the proliferation of variants of uncertain significance and the misinterpretation of variants.

  • genetic variation
  • neuromuscular diseases
  • diagnosis

Data availability statement

Data are available upon reasonable request.

https://doi.org/10.1136/jmg-2024-110019

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    Data availability statement

    Data are available upon reasonable request.

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    Footnotes

    • Contributors AGe designed and supervised the study, wrote the manuscript, and is the guarantor. AM, SP, ALB and PO performed the experiments. AGa set up the bioinformatics analysis. CP, FS, SM, MG and AS obtained consent from patients, and performed clinical evaluation and description. LM performed clinical evaluation and description. PM supervised the study, obtained consent from patients, performed clinical evaluation and description and helped write the manuscript. EB supervised the study, contributed to data extraction and helped write the manuscript. FG designed and supervised the study. All authors contributed to manuscript revision, and read and approved the final manuscript.

    • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

    • Competing interests None declared.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.