Novel VRK1 Variants and a Founder Effect in Axonal Polyneuropathy.

Area of Science:

• Genetics
• Neurology
• Molecular Biology

Background:

• Biallelic variants in the VRK1 gene are associated with various neurogenic disorders, including Charcot-Marie-Tooth related disease (CMTR), motor neuron diseases, and spinal muscular atrophy (SMA).
• Peripheral neuropathies represent a significant group of these disorders, necessitating further characterization of genetic causes and clinical manifestations.

Purpose of the Study:

• To investigate the genetic and clinical spectrum of VRK1-related peripheral neuropathy in a Chinese cohort presenting with axonal CMTR.
• To identify novel VRK1 variants and elucidate the underlying mechanisms and clinical heterogeneity in affected individuals.

Main Methods:

• Retrospective analysis of clinical and genetic data from eight families with axonal CMTR.
• Haplotype analysis to investigate the founder effect of a high-frequency VRK1 variant.
• RNA sequencing to analyze the impact of a splice site variant; systematic literature review to compile global cases.

Main Results:

• VRK1 was the third most common gene in the axonal recessive CMTR cohort, with ten variants identified, including eight novel ones.
• A founder effect was supported for the nonsense variant c.1124G>A (p.W375*), present in four families.
• Clinical phenotypes predominantly included distal hereditary motor neuropathy (dHMN) and axonal recessive CMT, with significant heterogeneity observed across 53 reported cases.

Conclusions:

• Identification of eight novel VRK1 variants expands the genotypic spectrum of VRK1-related peripheral neuropathy.
• Confirmation of a founder effect for p.W375* provides insights into the prevalence of specific variants in certain populations.
• The study highlights the clinical heterogeneity of VRK1-related disorders, primarily motor-dominant, aiding in diagnosis and management strategies.