Neuropathy due to bi-allelic SH3TC2 variants: genotype-phenotype correlation and natural history.

This article focuses on the clinical characteristics, genotype-phenotype correlations, and natural history of Charcot-Marie-Tooth disease type 4C (CMT4C), a recessive sensorimotor demyelinating polyneuropathy caused by biallelic variants in the SH3 domain and tetratricopeptide repeats 2 (SH3TC2) gene. Using longitudinal data from 56 individuals enrolled in the Inherited Neuropathy Consortium Rare Diseases Clinical Research Network (INC-RDCRN), the study found that CMT4C typically presents in childhood with moderate-to-severe disability, frequent scoliosis (81%), and walking difficulties (94%). Participants with two protein-truncating SH3TC2 variants showed more severe neurophysiological impairment and higher scoliosis prevalence compared to those with one or no truncating variants, suggesting milder phenotypes associated with some missense variants. The Charcot-Marie-Tooth Examination Score (CMTES) and its Rasch-weighted version (CMTES-R) demonstrated moderate responsiveness to disease progression over three years, supporting their use in clinical trial readiness for emerging gene therapies.