COG8 – COG8-congenital disorder of glycosylation

COG8-congenital disorder of glycosylation (CDG-IIh) is an autosomal recessive glycosylation defect characterized by multisystem involvement, including psychomotor retardation, hypotonia, failure to thrive, microcephaly, talipes equinovarus, and cerebellar atrophy. To date, three unrelated probands have been described ([PMID:28619360]), each harboring biallelic truncating mutations in COG8. In the index case, targeted exome sequencing identified two novel frameshift variants: c.171dupG (p.Leu58AlafsTer29) and c.1656dupC (p.Ala553ArgfsTer15), with parental segregation confirming trans inheritance ([PMID:28619360]). Biochemical assays revealed a type II transferrin isoelectric focusing profile consistent with defective Golgi glycosylation, and MRI demonstrated cerebellar atrophy, supporting a loss-of-function mechanism.

Inheritance is autosomal recessive, with compound heterozygous loss-of-function variants segregating in affected individuals. No additional affected relatives beyond probands have been reported, though parental carrier status was confirmed in each family. Variant spectrum to date comprises exclusively frameshift mutations predicted to truncate COG8, consistent across all cases. No recurrent or founder alleles have been identified, and carrier frequencies are not yet established.

Functional evidence is limited to biochemical profiling: transferrin glycoform analysis demonstrated increased disialo- and trisialo-transferrin species, confirming a glycosylation defect in patient serum ([PMID:28619360]). Histopathology showed mild interface hepatitis without significant fibrosis, reflecting variable hepatic involvement. Neuroimaging corroborated cerebellar degeneration, aligning with the clinical cerebellar atrophy. No cell or animal models or rescue experiments have been reported to date.

No reports to date dispute the association between biallelic COG8 loss-of-function variants and CDG-IIh. The clinical and biochemical concordance across the limited number of cases supports a pathogenic role for COG8 haploinsufficiency. Additional cohorts and functional studies would strengthen the mechanistic understanding.

In summary, compound heterozygous loss-of-function variants in COG8 cause a clinically recognizable CDG-IIh phenotype. This association currently meets a Moderate level of clinical validity with Moderate genetic evidence and Limited functional evidence. COG8 sequencing should be considered in patients with unexplained psychomotor retardation, hypotonia, skeletal deformities, and glycosylation abnormalities.

Key Take-home: Biallelic truncating COG8 variants underlie an autosomal recessive CDG-IIh syndrome, and molecular testing informs diagnosis and management.

References

• Clinica chimica acta; international journal of clinical chemistry • 2017 • Further delineation of COG8-CDG: A case with novel compound heterozygous mutations diagnosed by targeted exome sequencing. PMID:28619360

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