Genotype phenotype variability and genetic spectrum of inherited neuropathies in children

Genotype phenotype variability in inherited neuropathies

Abstract

Abstract

Objective

To characterize the clinical, electrophysiological, and genetic spectrum of inherited neuropathies (INs) in a pediatric cohort, emphasizing genotype-phenotype correlations and the role of whole-exome sequencing (WES) in genetic diagnosis.

Study Design

Cross-sectional observational study.

Place and Duration of Study

Pediatric Neurology Department, Children’s Hospital and University of Child Health Sciences, Lahore, Pakistan, from January 2017 to January 2023.

Materials and Methods

Twenty-eight pediatric patients (≤18 years) with genetically confirmed inherited neuropathies were enrolled. Clinical, electrophysiological, and genetic assessments were conducted. Nerve conduction studies classified neuropathies into axonal, demyelinating, or mixed subtypes. Whole-exome sequencing (WES) was performed in collaboration with UCL Institute of Neurology, London. Statistical analysis was performed with SPSS version 26 and p-value of 0.05 was considered significant.

Results

The cohort had a median symptom onset at 4 years (IQR: 2–6 years), with 96.4% consanguinity. Muscle atrophy (35.7%) and pes cavus (21.4%) were common. Electrophysiology classified neuropathies into demyelinating (28.6%), axonal (14.3%), and mixed (46.4%) subtypes. WES yielded a 68.29% diagnostic rate, with GAN and PDXK mutations (14.3% each) most common.

Conclusion

This study highlights the genetic heterogeneity of inherited neuropathies and the importance of WES for genetic diagnosis and targeted management, particularly in high-consanguinity populations.