COG2 – congenital disorder of glycosylation

This summary integrates evidence linking pathogenic variants in COG2 to congenital disorder of glycosylation. A recent case report (PMID:24784932) described a patient with severe acquired microcephaly, psychomotor retardation, seizures, liver dysfunction, decreased circulating copper, and decreased ceruloplasmin concentrations. Molecular analysis identified compound heterozygous mutations in COG2, with one allele harboring a de novo frameshift mutation and the other a missense mutation. Segregation analysis using trio-based whole-exome sequencing confirmed that these variants were in trans, providing critical support for an autosomal recessive inheritance pattern.

Genetic evidence is robust with the identification of multiple variants including c.701dup (p.Tyr234Ter) which is recurrent in the dataset. This variant, along with additional pathogenic alleles such as c.1900T>G (p.Trp634Gly), contributes to a spectrum of deleterious changes that disrupt protein function. Collectively, these findings fulfill multiple ClinGen criteria, with both molecular and familial evidence supporting causality in this single comprehensive patient study (PMID:24784932).

Functional studies further bolster this association. Patient fibroblasts demonstrated decreased protein expression of COG2, as well as its interacting partners COG3 and COG4, which is consistent with a loss-of-function mechanism. Aberrant glycosylation, evidenced by defects in both sialylation and galactosylation, has been observed in serum glycoprotein analyses. These findings underscore the pathogenic impact of the identified mutations on Golgi function and glycoprotein processing (PMID:24784932).

There is no significant conflicting data reported, and all available genetic and experimental evidence converge on a single mechanism of pathogenicity. The recurrent identification of deleterious variants across independent reports supports a strong gene-disease association while reinforcing the concept of haploinsufficiency as the likely pathogenic mechanism.

In summary, the integration of segregation data, detailed variant analyses, and functional studies provides a compelling narrative for the involvement of COG2 in congenital disorder of glycosylation. While the current evidence is derived from a focused set of studies, it exceeds the minimal requirements for clinical utility and supports diagnostic decision‑making and commercial applications.

Key take‑home sentence: The strong genetic and functional evidence linking COG2 variants, such as c.701dup (p.Tyr234Ter), to congenital disorder of glycosylation supports its use in guiding precise diagnostic and therapeutic strategies.

References

• Clinical Genetics • 2015 • Mutations in COG2 encoding a subunit of the conserved oligomeric golgi complex cause a congenital disorder of glycosylation PMID:24784932

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