Submission Details

COG4 was first reported in relation to autosomal recessive COG4-CDG by Reynders et al. in 2009 (PMID:19494034). At least 8 unique variants (missense and nonsense) have been reported in humans. Evidence supporting this gene-disease relationship includes both case-level data and experimental data.

Variants in this gene have been reported in at least 7 probands from 5 publications (PMIDs:19494034, 21185756, 34298581, 34022244). Patient symptoms include global developmental delay, seizures, axial hypotonia, limb hypertonia, microcephaly, deficiencies in both sialylation and galactosylation of N glycans, while patient fibroblasts revealed impaired O-glycosylation and a delay in Brefeldin A induced retrograde transport. No supporting segregation information is available. The disease mechanism appears to be biallelic loss-of-function. Heterozygous carriers are reportedly unaffected. This gene-disease relationship is supported by the biochemical function of COG4, which is a subunit of the conserved oligomeric Golgi (COG) complex, an octameric, specific tethering complex that is important to orchestrating retrograde vesicle targeting within the Golgi apparatus. Variants in 7 out of the 8 COG subunits have been found in patients with CDGs. COG4 has been shown to directly bind to the COG subunits COG1, COG2, COG5, and COG7 (PMID:15047703). Knock down of specific COG subunits have resulted in the mislocalization of Golgi glycosylation enzymes. These critical glycosylation enzymes are likely misplaced by impaired intra-golgi retrograde trafficking that effects Golgi enzyme replacement (PMID:31381138). Additionally, the gene-disease relationship is supported by knockdown COG4 HeLa cells, which recapitulated two phenotypes associated with COG4-CDG, reduced COG4 protein levels and a significant delay in BFA-induced redistribution of Golgi remnants (PMID:19494034). Furthermore, addition of COG4-WT to knock down COG4 HeLa cells rescued a glycosylation defect (PMID:19651599). Finally, COG4 mutation analysis in S. cerevisiae revealed that COG4 mutants secreted increased carboxypeptidase Y (CPY), a sensitive indicator of vacuolar protein sorting trafficking defects (PMID:19651599). In summary, there is moderate evidence to support this gene-disease relationship. Although more evidence, genetic and experimental, is needed to support a causal role, no convincing evidence has emerged that contradicts the gene-disease relationship. A classification of moderate was approved by the ClinGen Congenital Disorders of Glycosylation GCEP on 05/17/2023 (SOP Version 9).