COG4

Inheritance Pattern: AD

Disease ID:MONDO:0019407

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0013281

Submitter: ClinGen

*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).

Inheritance Pattern: AD

Disease ID:MONDO:0019407

Submitter: ClinGen

Saul Wilson syndrome (SWS) was first reported by Saul and Wilson in 1990 (PMID:2309787). Later, Ferreira et al. found that Saul Wilson syndrome is caused by a *COG4* heterozygous de novo variant p.Gly516Arg (c.1546G>A or c.1546G>C, PMID:30290151). Saul Wilson syndrome is a rare skeletal dysplasia characterized by a unique set of phenotypes including but not limited to short stature, progeroid facial appearance, prominent eyes, cataracts, micrognathia, platyspondyly, irregular end plates of vertebral bodies, speech and motor delays, coxa valga, blue sclerae, narrow nasal bridge with a convex nasal ridge, brachydactyly, and early developmental delay. Molecularly, patient fibroblasts demonstrate impaired Golgi to ER vesicle trafficking including an increase in retrograde trafficking and an apparent decrease in anterograde trafficking from Brefeldin A trafficking assays. Additionally, many SWS patients show abnormal Golgi architecture and collapsed Golgi stacks. In total, 15 individuals have been identified with Saul Wilson syndrome and the *COG4* p.Gly516Arg variant from two publications (PMIDs: 30290151, 35455576). Importantly, a decision to split this curation from autosomal recessive *COG4*-CDG (moderate classification) was made based upon significant differences in molecular mechanism, clinical phenotypes, and mode of inheritance by the CDG GCEP. This gene disease relationship is supported by experimental evidence including the biochemical function of *COG4*, a subunit of the octameric COG complex, which is a specific tethering complex that is important to orchestrating retrograde and anterograde vesicle trafficking by interacting with several proteins including SNARES, Rab GTPases, and COPI coat protiens (PMID:30290151). Additionally, the p.Gly516Arg variant has been expressed into Zebrafish embryos and a chrondocyte-like cell line. In Zebrafish embryos, the p.Gly516Arg variant recapitulated molecular phenotypes observed in SWS fibroblasts including an increase in glypicans and elevated wnt4 transcripts, while showing additional phenotypes such as shortened embryonic anterior–posterior body axis and embryonic defects in chondrocyte morphogenesis (PMID: 34595172). Meanwhile, in a chrondocyte-like cell line, expression of p.Gly516Arg recapitulated phenotypes observed in SWS fibroblasts such as accelerated Brefeldin A (BFA)-induced retrograde transport and increased apoptosis in a 3D pellet culture, while also showing impaired chondrogenic differentiation and an inability to form spheroids in the presence of BMP2 (PMID:36393834). In summary *COG4* is definitively associated with autosomal dominant Saul Wilson Syndrome. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Skeletal Disorders GCEP on the meeting date 06/05/2023 (SOP Version 9).

Inheritance Pattern: AD

Disease ID:MONDO:0019407

Submitter: Labcorp Genetics (formerly Invitae)

Inheritance Pattern: AR

Disease ID:MONDO:0013281

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0013281

Submitter: Ambry Genetics

Inheritance Pattern: AD

Disease ID:MONDO:0019407

Submitter: Ambry Genetics

Inheritance Pattern: AR

Disease ID:MONDO:0019407

Submitter: Orphanet

Inheritance Pattern: AR

Disease ID:MONDO:0013281

Submitter: G2P

Inheritance Pattern: AR

Disease ID:MONDO:0013281

Submitter: Labcorp Genetics (formerly Invitae)