Novel <i>VRK1</i> Variants and a Founder Effect in Axonal Polyneuropathy

Background and Objectives: -related peripheral neuropathy in a Chinese cohort with axonal CMTR. Methods: Eight families were identified from a cohort of 351 families with axonal CMTR, including axonal CMT and distal hereditary motor neuropathies (dHMN). Clinical and genetic data were retrospectively analyzed. Haplotype analysis investigated the founder effect of the high-frequency variant, and RNA sequencing was conducted for the splice variant. A systematic literature review (PubMed/CNKI, 2009-2025) was performed to compile global cases. Results: variants were identified, including 8 novel variants: c.7C>T, c.83T>G, c.215T>G, c.539C>T, c.879_882del, c.974T>A, c.1073_1076del, and c.1159+2T>A. The nonsense variant c.1124G>A (p.W375*) was present in 4 of 8 families with haplotype analysis supporting a founder effect. RNA sequencing confirmed c.1159+2T>A caused exon 12 skipping and frameshift (p.K357Vfs*39). The clinical phenotypes included dHMN in 7 cases and axonal recessive CMT in one case. Two patients with dHMN exhibited upper motor neuron signs. All patients presented with progressive distal lower limb weakness, without neurodevelopmental impairment. In total, 53 cases from 37 families reported to date (including the present cohort) revealed substantial clinical heterogeneity, with dHMN (28.8%) and SMA (26.9%) being most common. Early-onset cases exhibited rapid progression, whereas later-onset cases had slower courses. Discussion: -related peripheral neuropathy and provide valuable insights for accurate diagnosis and management.