To describe a novel de novo mutation in a case of GNE myopathy and describe the associated inherent diagnostic challenges.

GNE myopathy is a rare cause of insidious progressive distal lower extremity weakness and atrophy presenting in early adulthood. This myopathy is inherited in an autosomal recessive pattern and phenotypic presentation is caused by biallelic pathogenic mutations in the GNE gene. Mild serum creatinine kinase elevations can be seen along with histopathologic features of muscle fiber atrophy, rimmed vacuoles, and lack of inflammation. There are well-documented founder mutations from different geo ancestral populations. Currently, clinical studies of several gene-based therapies are underway.

A 20-year-old Indo-Caribbean man presented with progressive distal lower extremity predominant weakness and atrophy for the past four years.  An electromyogram disclosed a diffuse myopathic process with sparing of the quadriceps. Serial creatinine kinase levels were between 700-900 U/L. Muscle biopsy of the left gastrocnemius revealed muscle fiber atrophy with no evidence of inflammation, rimmed vacuoles, or muscle fiber regeneration.

Genetic sequencing panel and deletion/ duplication analysis revealed one heterozygous pathogenic sequence variant in the GNE gene (DNA change c.2179G>A, protein change p.Val727Met). Whole genome sequencing revealed a small additional GNE intron1 deletion (11501 bp at chr9:36,256,763-36,268,263), which had not been previously reported as causative in literature review. Additional genetic testing was pursued in the patient’s parents to definitively confirm a biallelic inheritance pattern and pathogenic state.

Although primary genetic sequencing revealed a mutation in only one allele, this case demonstrated the utility of advanced genetic investigation that ultimately revealed a small hidden intron variation that confirmed genetic causation for the patient’s phenotypic presentation. This additionally provided the patient an opportunity for disease trial enrollment.