COG6 – COG6-congenital disorder of glycosylation

The association between COG6 and COG6-congenital disorder of glycosylation is classified as Strong based on ClinGen criteria. Eighteen unrelated patients have been reported with biallelic COG6 variants causing CDG2L (PMID:35068072), with functional complementation restoring Golgi transport in patient fibroblasts (PMID:20605848).

COG6-CDG is inherited in an autosomal recessive pattern. To date, over 28 patients across multiple consanguineous families and sibships have been identified with homozygous or compound heterozygous variants (PMID:40213872). Variant types include missense (e.g., c.1646G>T (p.Gly549Val) (PMID:20605848)), nonsense (c.388C>T (p.Gln130Ter) (PMID:29709711)), frameshift (c.823delA (p.Ser275ValfsTer32) (PMID:35068072)), splice-site (c.518_540+3del) and in-frame deletions (c.1141_1143del (p.Leu381del) (PMID:35068072)). Segregation analysis in consanguineous pedigrees and sibling cohorts accounts for at least 4 additional affected relatives beyond index cases.

Functional studies demonstrate that COG6 deficiency disrupts N- and O-glycosylation, evidenced by HPLC and mass spectrometry of transferrin oligosaccharides, Western blot and gel filtration showing COG complex fragmentation, and RT-PCR confirming aberrant transcripts subject to nonsense-mediated decay (PMID:40225945). Retroviral complementation of patient fibroblasts with wild-type COG6 cDNA normalized retrograde Golgi transport after Brefeldin A treatment (PMID:20605848).

No studies to date have disputed the COG6-CDG association or reported phenotypes incompatible with glycosylation defects. The mechanistic evidence supports a loss-of-function/haploinsufficiency model.

In summary, biallelic COG6 variants cause a definitive autosomal recessive congenital disorder of glycosylation characterized by neurodevelopmental delay, microcephaly, multisystem involvement and glycosylation abnormalities. Genetic testing of COG6 informs diagnosis, carrier screening, and potential prenatal counseling. Key Take-home: COG6-CDG is a clinically actionable, autosomal recessive glycosylation disorder with strong genetic and functional evidence linking COG6 loss to multisystem pathology.

References

• Human molecular genetics • 2010 • Fatal outcome due to deficiency of subunit 6 of the conserved oligomeric Golgi complex leading to a new type of congenital disorders of glycosylation PMID:20605848
• European journal of medical genetics • 2019 • Compound heterozygous variants of the COG6 gene in a Chinese patient with deficiency of subunit 6 of the conserved oligomeric Golgi complex (COG6-CDG) PMID:29709711
• Birth defects research • 2022 • COG6-CDG: Novel variants and novel malformation PMID:35068072
• Molecular genetics & genomic medicine • 2025 • COG6-related prenatal phenotype (CDG2L): Clinico-pathological report and review of the literature PMID:40213872
• Human mutation • 2024 • COG6-CDG: Two Novel Variants and Milder Phenotype in a Chinese Patient PMID:40225945

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