P.3.5 Identification of rare variants in GNE and other sialic biosynthetic genes in HIBM2 and sIBM

Abstract

Hereditary inclusion body myopathy type 2 (HIBM2) or GNE Myopathy is associated with mutations in the GNE gene that encodes the bifunctional protein essential for sialic acid biosynthesis, UDP-GlcNAc 2-epimerase/N-acetylmannosamine kinase. Whether mutations in GNE or other genes within the sialic acid pathway are associated with hereditary or sporadic muscle diseases such as sporadic inclusion body myositis (sIBM) is not known. More importantly whether these disorders will be amenable to oral sialic acid treatment is not established. We performed targeted next generation sequencing of the whole GNE locus and the coding regions of three other genes essential for sialic acid synthesis (NANS N-acetylneuraminic acid phosphate synthase; NANP Neu5Ac-9-phosphate phosphatase; CMAS CMP-Neu5Ac synthetase) that have not previously been reported to be associated with muscle disease in 78 patients with sIBM and 9 patients with presumed HIBM. Using this strategy, we identified compound heterozygous mutations in the GNE gene in 5 of 9 HIBM patients, one of which was novel. Interestingly, two of these patients had been previously characterized as sIBM despite being siblings, two were referred for spinal muscular atrophy, and one with an undiagnosed HIBM. Moreover, two of these five patients had been previously reported to be sequenced for GNE mutations and found to be negative. The minor allele of two GNE intronic SNPs was statistically overrepresented in our cohort compared to population controls. Of the 78 sIBM patients, one was heterozygous for a rare missense variant in GNE and three were heterozygous for rare missense variants in NANS. Coding mutations in GNE, NANS, NANP and CMAS are rare in sIBM patients. Any patient with a family history of sIBM or clinical suspicion in the setting of negative genetic testing should be tested/retested for GNE mutations. Next generation sequencing may identify mutations previously undetected by traditional sequencing methods.