Normal transferrin patterns in congenital disorders of glycosylation with Golgi homeostasis disruption: apolipoprotein C-III at the rescue!

Abstract We identified three cases of congenital disorders of glycosylation (CDG) with Golgi homeostasis disruption, one ATP6V0A2-CDG and two COG4-CDG, with false-negative transferrin screening analyses. Patient 1 (P1) presented at birth with cutis laxa. Patient 2 (P2) and patient 3 (P3) are adult siblings and presented with severe symptoms evocative of inborn errors of metabolism. Targeted gene sequencing in P1 revealed pathogenic ATP6V0A2 variants, shared by her affected older brother. In P2 and P3, whole exome sequencing revealed a homozygous COG4 variant of unknown significance. In all affected individuals, transferrin analysis was normal. Mass-spectrometry based serum N-glycome analysis and two-dimensional electrophoresis (2-DE) of haptoglobin and of mucin core 1 O-glycosylated apolipoprotein C-III (apoC-III) were performed. All results of second-line N-glycosylation analyses were initially normal. However, apoC-III 2-DE revealed characteristic “apoC-III1” pattern in P1 and specific “apoC-III0” patterns in P2 and P3. In P2 and P3, this allowed reclassifying the variant as likely pathogenic according to ACMG guidelines. These cases highlight the existence of normal transferrin patterns in CDG with Golgi homeostasis disruption, putting the clinicians at risk of wrongly misdiagnosing patients. Furthermore, they show the potential of apoC-III 2-DE in diagnosing this type of CDG, with highly specific patterns in COG-CDG.