Search for Additional Pathogenic Variants to Explain Variation in PMP22-Related Neuropathies

The aim of this study was to investigate whether the considerable phenotypic variation in Charcot-Marie-Tooth disease type 1A (CMT1A) and hereditary neuropathy with liability to pressure palsies (HNPP) is due to additional pathogenic coding variants in severely affected patients, by screening a panel of neuropathy-related genes.

In this cross-sectional study, the extremes of the spectrum of 742 patients with genetically confirmed CMT1A and HNPP were selected, based on disability as assessed using the Overall Neuropathy Limitation Scale (ONLS). The ONLS data of 183 patients with CMT1A and 102 with HNPP showed a Gaussian distribution. A next-generation sequencing panel containing 177 neuropathy-related genes was tested in a selected group of 20 patients with mild CMT1A, 24 with severe CMT1A, 25 with mild HNPP, and 25 with severe HNPP.

One additional autosomal dominant pathogenic variant in the MFN2 gene was identified in a severe CMT1A case. Heterozygous pathogenic variants in autosomal recessive neuropathy-related genes were found in 2 patients with severe CMT1A and in 2 with mild HNPP.

In our study, additional pathogenic coding variants in neuropathy-related genes did not contribute to variation in disease severity in most patients with CMT1A and HNPP. In cases with confirmed PMP22 copy-number alterations, further genetic screening for pathogenic variants in CMT-related genes is warranted only in severe cases.