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 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.