Digenesis in Charcot-Marie-Tooth Disease: Impact of Combined Mutations in the MFN2 and GDAP1 Genes

Charcot-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.

We 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.

Out 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.

The 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.