Overlapping phenotype of GNE myopathy and dystrophinopathy: a rare case with dual variants from India

Distal myopathies are rare neuromuscular disorders, among which GNE myopathay (also known as Nonaka myopathy) results from autosomal recessive mutations in the GNE [glucosamine (UDP-N-acetyl)-2-epimerase/N-acetylmannosamine kinase] gene, while Duchenne muscular dystrophy (DMD), the most common form, is caused by X-linked recessive mutations in the DMD gene. We describe a rare case of overlapping pathogenic variants in both genes, leading to an atypical phenotype. A 24-year-old Indian male with a history of progressive muscle weakness since childhood was evaluated. Clinical assessment, serum creatine phosphokinase (CK) testing, multiplex ligation-dependent probe amplification (MLPA) for DMD, whole exome sequencing (WES), Sanger sequencing, and genomic DNA–based real-time PCR were performed. Family segregation analysis was also undertaken. The patient presented with progressive quadriparesis, myalgia, hypotonia, and bent fingers (camptodactyly), and had been wheelchair-bound for 12 years. CK was moderately elevated (285 U/L) when measured at 22 years of age. MLPA analysis did not detect any exonic deletions or duplications in DMD. WES revealed a hemizygous novel pathogenic variant in DMD (c.3163 A > T; p.Asn1055Tyr), a heterozygous missense variant in GNE (c.2086G > A; p.Val696Met), and a heterozygous deletion in exon 11 of GNE (9p13.3). SNVs were validated by Sanger sequencing and the CNV by genomic DNA based real-time PCR. Segregation analysis demonstrated maternal inheritance of the DMD variant, paternal inheritance of the GNE missense variant, and a proband-specific GNE deletion. This case represents a rare example of early onset distal myopathy with concurrent pathogenic variations in both DMD and GNE. The coexistence of multiple variants highlights a possible synergistic effect contributing to the unique clinical phenotype observed.