A Case Report of a Pedigree with Distal Hereditary Motor Neuropathy Caused by a Homozygous c.1124G>A Variant an the /*9Vaccinia-Related Kinase 1 Gene

Summary

This study reports a Chinese consanguineous pedigree with adult-onset distal hereditary motor neuropathy (dHMN) caused by a homozygous c.1124G>A variant in the vaccinia-related kinase 1 (VRK1) gene. The findings expand the clinical phenotypic and genetic spectrum of VRK1-related dHMN in the Chinese population.

Abstract

This study aimed to analyze the clinical phenotypes, neurophysiological characteristics, and pathogenicity of gene variants in a pedigree with distal hereditary motor neuropathy (dHMN) caused by VRK1 variants, and to provide evidence to support clinical diagnosis and genetic counseling for this disease. We report a Chinese consanguineous family with dHMN caused by a homozygous c.1124G>A variant in the VRK1 gene. Clinical and electrophysiological data of the proband were collected. Whole-exome sequencing (WES) and validation by Sanger sequencing were performed to identify the variant site, and pathogenicity interpretation was conducted in accordance with American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines. The proband was a 24-year-old male who presented with 2 years of progressive weakness and atrophy of the distal lower limbs, accompanied by slender upper limbs and no sensory disturbance. Electrophysiological examination showed decreased compound muscle action potential (CMAP) amplitude in motor nerves of both upper and lower limbs, indicating peripheral neurogenic damage, while sensory nerve conduction was normal. Genetic testing detected a homozygous c.1124G>A (p.Trp375Ter) variant in the VRK1 gene. His parents and elder sisters were heterozygous carriers, and the pedigree conformed to autosomal recessive inheritance. According to ACMG guidelines, this variant was classified as pathogenic (evidence: PVS1, PM2, PP1). The homozygous VRK1 c.1124G>A variant causes adult-onset dHMN, rather than pontocerebellar hypoplasia type 1A (PCH1A) as annotated in some genetic databases. This pedigree presents distinctive phenotypes, including slender upper limbs and diffusely decreased CMAP amplitudes in both upper and lower limbs, thereby expanding the clinical and genetic spectrum of VRK1-related dHMN in the Chinese population.

Introduction

Distal hereditary motor neuropathy (dHMN) constitutes a genetically heterogeneous group of inherited peripheral nervous system disorders, defined pathologically by length-dependent degeneration of lower motor neurons and their axons. Clinically, patients present with progressive weakness and atrophy of the distal limb muscles, while sensory function remains largely intact in most cases¹. Initial manifestations typically affect the distal lower limbs, including toe flexion weakness and atrophy of the gastrocnemius and intrinsic foot muscles, with gradual progression to involve the interosseous muscles of the hand and thenar/hypothenar muscles as....

Protocol

This study was approved by the Ethics Committee of Yunnan Provincial Hospital of Traditional Chinese Medicine (approval number: YYLW-2026-006). Written informed consent was obtained from the proband and all participating family members prior to enrollment.

1. Participant preparation and clinical assessment

1. The proband and available family members were enrolled after written informed consent was obtained.
2. Detailed demographic information, disease history, family history, and consanguinity information were collected using a standardized questionnaire.
3. A systematic neurological examination was p....

Results

Genetic findings

WES was performed on the proband, with a mean target region depth of 112 ×; 98.7% of target bases were covered at ≥10 × depth, and 96.2% at ≥20 × depth. After variant filtering and prioritization, a homozygous nonsense variant c.1124G>A (p.Trp375Ter) in the VRK1 gene (transcript NM_003384.3, genome build GRCh37/hg19) was identified as the candidate pathogenic variant.

Sanger sequencing confirmed that the proband carried .......

Discussion

In this study, we applied an integrated diagnostic workflow combining clinical phenotyping, neurophysiological examination, WES, and familial segregation analysis to identify a homozygous VRK1 c.1124G>A pathogenic variant in a Chinese consanguineous family with adult-onset dHMN. This pedigree broadens the phenotypic spectrum of VRK1-related disorders and provides reference data for diagnosing dHMN in the Chinese population.

Methodological considerations for the diagnostic .......

Materials

List of materials used in this article

Name	Company	Catalog Number	Comments
Reagents & Consumables
EDTA anticoagulant vacuum blood collection tube (5 mL)	BD Biosciences (Becton, Dickinson and Company)	367861
Genomic DNA Extraction Kit (spin-column format) for peripheral blood	QIAGEN; QIAamp DNA Blood Mini Kit	51106
Multiplex Ligation-dependent Probe Amplification (MLPA) Kit	MRC Holland	Custom probe set for target gene
PCR Amplification Kit (Taq polymerase, dNTPs, reaction buffer included)	Takara Bio; LA Taq PCR Kit	RR002A
Agarose powder (electrophoresis grade)	Biowest	111860
Sanger Sequencing Reaction Kit (BigDye Terminator v3.1)	Thermo Fisher Scientific; Applied Biosystems	4337455
Sequencing Product Purification Kit	Thermo Fisher Scientific; BigDye XTerminator Purification Kit	4376484
TAE electrophoresis buffer	Commercial grade / laboratory-prepared	—
PCR 8-strip tubes, centrifuge tubes and other routine consumables	Axygen	—
Instruments & Equipment
Capillary electrophoresis genetic analyzer (Sanger sequencing platform)	Applied Biosystems, Thermo Fisher Scientific	3500 Dx
Gradient thermal cycler (PCR instrument)	Bio-Rad Laboratories	C1000 Touch
Ultramicro spectrophotometer (for nucleic acid quantification)	NanoDrop One, Thermo Fisher Scientific	ND-ONE-W
Horizontal agarose gel electrophoresis system	Beijing Liuyi Biotechnology Co., Ltd.	DYY-6C
Gel documentation and analysis system	Bio-Rad Laboratories	GelDoc Go
Benchtop high-speed refrigerated centrifuge	Eppendorf	5424 R
Nerve conduction velocity / electromyography (NCV/EMG) system	Natus Medical	Keypoint 9033A07
Constant temperature metal bath / water bath	DLAB Scientific	—
Analysis Software
MLPA data analysis software (Coffalyser.Net)	MRC Holland	v140
Sanger sequencing peak analysis and sequence alignment software	Applied Biosystems, Thermo Fisher Scientific	Sequencing Analysis v6.0
Primer design software	Premier Biosoft	Primer Premier 6
Sequence alignment and variant interpretation tools	NCBI BLAST (online), ClinVar database	—