Novel VRK1 Variants and a Founder Effect in Axonal Polyneuropathy

Biallelic VRK1 variants are linked to a range of neurogenic disorders, including Charcot-Marie-Tooth and related disease (CMTR), motor neuron diseases, and spinal muscular atrophy (SMA). This study aimed to characterize the genetic and clinical features of VRK1-related peripheral neuropathy in a Chinese cohort with axonal CMTR.

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.

VRK1 was the third most common gene in our axonal recessive CMTR cohort. Ten VRK1 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.

This study identifies 8 novel VRK1 variants and confirms the founder effect of p.W375*, expanding the genotypic and phenotypic spectrum of VRK1-related peripheral neuropathy. The clinical presentation in this cohort was predominantly motor-dominant, ranging from dHMN to axonal CMT, with notable phenotypic heterogeneity influenced by the specific protein domain involved. These findings refine the understanding of VRK1-related peripheral neuropathy and provide valuable insights for accurate diagnosis and management.