ArticleJournal of the peripheral nervous system : JPNS2025
Digenesis in Charcot-Marie-Tooth Disease: Impact of Combined Mutations in the MFN2 and GDAP1 Genes.
Article in Journal of the peripheral nervous system : JPNS, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 2 papers.
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2 citing papers in PubMed.
- Unraveling GDAP1: Bridging Mitochondrial Biology and Peripheral Neuropathy.Biomolecules · 2026Review
- Digenesis in Charcot-Marie-Tooth Disease: Impact of Combined Mutations in the MFN2 and GDAP1 Genes.Journal of the peripheral nervous system : JPNS · 2025Article
Corrections and comments
- Erratum issued
Authors and funding
11 authors.
Funding
No grant is acknowledged in the PubMed record.
Abstract
BACKGROUND AND
aimsCharcot-Marie-Tooth disease (CMT) is a rare hereditary neuropathy that affects peripheral nerves in the upper and lower limbs. To distinguish between the different forms of the disease, electrophysiological criteria are essential. Furthermore, identifying the genetic cause is crucial for providing accurate genetic counseling. The genetic complexity of CMT is partly explained by digenism, where mutations in two distinct genes might contribute to the disease. Two genes involved in mitochondrial dynamics, MFN2 and GDAP1, have been identified in digenic cases of CMT. This retrospective study reports MFN2/GDAP1 digenism cases identified in patients affected by CMT in our laboratory.
methodsWe conducted a retrospective analysis of 1665 patients who underwent NGS using the CMT gene panel between 2016 and 2024. These patients affected by CMT were addressed from neurology reference centers in France. The results were analyzed with bioinformatics tools, initially using the hg19 reference genome and then the hg38 version.
resultsOut of 1665 patients, 367 positive cases were identified, corresponding to a 22% molecular diagnostic rate, excluding PMP22 duplications. Among these, 15 cases involved variants in two distinct genes, resulting in a 4% digenism rate. Five cases involved MFN2/GDAP1 variants, accounting for 1.4% of the total positive results and 33% of all digenic cases.
interpretationThe cases of digenism have a significant prevalence in CMT disease and may explain the severity of the phenotype in our patients. Multilocus variants complicate genetic counseling due to non-Mendelian inheritance. In addition, it is important to distinguish between digenism and modifier genes.
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