COG5-congenital disorder of glycosylation diagnosed by whole genome sequencing in siblings with unexplained optic atrophy, macular atrophy, and developmental delay: case report.

INTRODUCTION

COG5-related congenital disorder of glycosylation (COG5-CDG) is a rare autosomal recessive metabolic disorder with variable neurologic and ophthalmologic involvement. We report two siblings presenting with optic atrophy, macular atrophy, and neurodevelopmental delay; these three phenotypic manifestations have not, to our knowledge, been combined together in previously described individuals with COG5-CDG. The genetic disorder was only diagnosed through whole genome sequencing (WGS) after panel-based exome testing was unrevealing.

CLINICAL FINDINGS: Both siblings presented with early-onset severe visual impairment, bilateral optic atrophy, central macular atrophy, sensory nystagmus, and strabismus in the setting of global developmental delay. Additional features included polymicrogyria and hypotonia (Case 1) and microcephaly and autism spectrum disorder (Case 2).

DIAGNOSES AND OUTCOMES: After repeated non-diagnostic inherited retinal gene panels, clinical quad WGS identified compound heterozygous variants in COG5 in both siblings: a paternally inherited pathogenic frameshift variant (c.1415dup) and a maternally inherited deep intronic variant (c.417 + 4779A>G) with high SpliceAI-predicted splicing impact. Visual function has remained relatively stable over 5 years of follow-up.

CONCLUSION

These cases expand the phenotypic spectrum of COG5-CDG to include concurrent optic nerve and macular involvement with neurodevelopmental impairment and highlight the essential role of WGS in diagnosing complex neuro-ophthalmologic presentations when targeted genetic testing is nondiagnostic.