Novel variants and genotype-phenotype correlation in a multicentre cohort of GNE myopathy in China

J Med Genet. 2024 Oct 23;61(11):1053-1061. doi: 10.1136/jmg-2024-110149.

Abstract

Background: GlcNAc2-epimerase (GNE) myopathy is a rare autosomal recessive disorder caused by pathogenic variants in the GNE gene, which is essential for the sialic acid biosynthesis pathway.

Objective: This multi-centre study aimed to delineate the clinical phenotype and GNE variant spectrum in Chinese patients, enhancing our understanding of the genetic diversity and clinical manifestation across different populations.

Methods: We retrospectively analysed GNE variants from 113 patients, integrating these data with external GNE variants from online databases for a global perspective, examining their consequences, distribution, ethnicity and severity.

Results: This study revealed 97 distinct GNE variants, including 35 (36.08%) novel variants. Two more patients with deep intronic variant c.862+870C>T were identified, while whole genome sequencing (WGS) uncovered another two novel intronic variants: c.52-8924G>T and c.1505-12G>A. Nanopore long reads sequencing (LRS) and further PCR analysis verified a 639 bp insertion at chr9:36249241. Missense variants predominantly located in the epimerase/kinase domain coding region, indicating the impairment of catalytic function as a key pathogenic consequence. Comparative studies with Japanese, Korean and Jewish, our cohorts showed later onset ages by 2 years. The high allele frequency of the non-catalytic GNE variant, c.620A>T, might underlie the milder phenotype of Chinese patients.

Conclusions: Comprehensive techniques such as WGS and Nanopore LRS warrants the identifying of GNE variants. Patients with the non-catalytic GNE variant, c.620A>T, had a milder disease progression and later wheelchair use.

Keywords: genetic variation; genotype; neuromuscular diseases.

Publication types

  • Multicenter Study

MeSH terms

  • Adolescent
  • Adult
  • Carbohydrate Epimerases / genetics
  • Child
  • Child, Preschool
  • China / epidemiology
  • Distal Myopathies / epidemiology
  • Distal Myopathies / genetics
  • Distal Myopathies / pathology
  • East Asian People / genetics
  • Female
  • Genetic Association Studies* / methods
  • Humans
  • Male
  • Mutation
  • Phenotype
  • Retrospective Studies
  • Whole Genome Sequencing
  • Young Adult

Substances

  • Carbohydrate Epimerases
  • UDP-N-acetylglucosamine 2-epimerase - N-acetylmannosamine kinase

Supplementary concepts

  • Distal myopathy, Nonaka type