Novel Pathogenic Variants in a French Cohort Widen the Mutational Spectrum of GNE Myopathy

Background: GNE myopathy is a rare autosomal recessively inherited muscle disease resulting from mutations in the gene encoding GNE (UDP-N-acetylglucosamine-2-epimerase/N-acetylmannosamine kinase), a key enzyme in sialic acid biosynthesis. 154 different pathogenic variants have been previously associated with GNE myopathy.

Objective: Describe novel pathogenic variants associated with GNE myopathy in a large French cohort.

Methods: We analyzed mutational data from 32 GNE myopathy index patients. Novel, as well as previously published pathogenic variants, were examined for possible deleterious effects on splicing.

Results: We describe 13 novel pathogenic variants in GNE, identified in the first large French cohort reported to date. We also find that 6 published pathogenic variants might have a previously unrecognized deleterious effect on splicing.

Conclusions: Novel pathogenic GNE variants described here raise the total number of different pathogenic variants reported to 167, complementing the recently published GNE mutation update. Our novel findings on possible splice-disrupting effects by several variants suggest that the pathogenicity mechanism of these variants could be reinterpreted, expanding our knowledge about the GNE mutational spectrum.