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

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

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

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

Results: This study revealed 97 distinct 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 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 variants. Patients with the non-catalytic variant, c.620A>T, had a milder disease progression and later wheelchair use.