Submission Details

PRX was first reported in relation to autosomal Charcot-Marie-Tooth disease type 4 in 2001 in a large consanguineous Lebanese family (Guilbot et al., PMID: 11157804). Patients had severe and slowly progressive demyelinating CMT with onset in early childhood. A homozygous stop-gain variant, Arg196X, segregated in the affected individuals. Linkage analysis revealed a LOD score of 5.3. PRX mutations have also been frequently reported in patients diagnosed with Dejerine Sottas neuropathy (Boerkoel et al., PMID: 11133365). Both phenotypes are part of the same disease spectrum consisting of early-onset severe demyelinating motor and sensory neuropathy. Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, and phenotypic variability. Therefore, the following disease entities have been lumped into one disease entity, autosomal recessive CMT type 4. Ten families with biallelic loss-of-function variants (nonsense and frameshift) from different publications have been included in this curation. Most variants are localized to the last exon and escape nonsense mediated mRNA decay. Expression of a truncated protein was detected in patient nerve biopsies (PMID: 12112076). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is not known. This gene-disease association is also supported by a PRX knockout mouse model, which developed an unsteady gait phenotype and demyelinating motor and sensory neuropathy (PMID: 10839370). In summary, the final classification for PRX is definitive. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time.