COG5 – COG5-congenital disorder of glycosylation (CDG)

COG5 (HGNC:14857) encodes a subunit of the conserved oligomeric Golgi (COG) complex crucial for Golgi trafficking and glycosylation. Biallelic COG5 variants cause a rare autosomal recessive congenital disorder of glycosylation (MONDO:0013325), characterized by neurological impairment and multisystem involvement.

Autosomal recessive inheritance is supported by two unrelated probands: one Chinese male with compound heterozygous variants and one Tunisian patient homozygous for a missense allele. Parental testing confirmed segregation of each allele ([PMID:31572517]; [PMID:38987656]). No additional affected relatives were reported.

Three pathogenic variants have been described: c.330delT (p.Val111LeufsTer22) novel frameshift, c.2324C>T (p.Ser775Phe) recurrent missense, and c.298C>T (p.Leu100Phe) homozygous missense. These include two missense and one loss-of-function allele, each expected to disrupt COG5 activity.

Functional studies of the p.Leu100Phe variant demonstrate reduced protein solubility and stability and abrogation of COG5–COG7 interaction in patient-derived cells via co-immunoprecipitation ([PMID:38987656]). In silico analyses of conserved residues further support a deleterious effect on COG complex integrity.

No animal models have been reported, but concordant biochemical and cellular data align with patient phenotypes of hypotonia (HP:0001252), global developmental delay (HP:0001263), and skin abnormalities (HP:0000951). These findings support COG5 haploinsufficiency and destabilizing missense effects as the mechanism of pathogenicity.

Taken together, limited genetic evidence from two probands combined with moderate functional data establishes a Limited clinical validity for COG5-CDG. Further case series and extended segregation studies will strengthen this association.

Key take-home: Biallelic COG5 variants cause autosomal recessive CDG via loss of Golgi complex stability, warranting inclusion in diagnostic glycosylation panels.

References

• Experimental and therapeutic medicine • 2019 • Novel compound heterozygous COG5 mutations in a Chinese male patient with severe clinical symptoms and type IIi congenital disorder of glycosylation: A case report. PMID:31572517
• Journal of human genetics • 2024 • Characterization of a missense variant in COG5 in a Tunisian patient with COG5-CDG syndrome and insights into the effect of non-synonymous variants on COG5 protein. PMID:38987656

Evidence Based Scoring (AI generated)