COG5 – Congenital Disorder of Glycosylation

The COG5 gene encodes a subunit of the Conserved Oligomeric Golgi (COG) complex, which plays an essential role in intra‐Golgi retrograde trafficking. Disruption of COG5 function through various mutations impairs glycosylation processes and interferes with proper protein sorting. Multiple independent studies have reported patients with congenital disorders of glycosylation (CDG) carrying COG5 mutations, with clinical presentations ranging from mild to moderate neurological impairment. This evidence supports a strong link between COG5 and CDG, impacting patient management and differential diagnosis (PMID:19690088).

Several case reports demonstrate the genetic basis of CDG associated with COG5 variants. A homozygous intronic splicing mutation, among other variant types, was identified by sequence analysis in patients presenting with delayed motor and language development (PMID:19690088). Additional reports have described compound heterozygous and homozygous alterations, including a reported variant, c.1290C>A (p.Phe430Leu), which satisfies the criteria for full coding changes with accurate HGVS nomenclature (PMID:32174980). The aggregation of independent observations across unrelated families supports robust genetic evidence for this disease association.

The inheritance pattern for CDG caused by COG5 mutations is autosomal recessive, as demonstrated by segregation analyses in several studies. In these families, affected individuals typically received one mutant allele from each parent, leading to compromised protein function. Although the precise count of additional affected relatives with segregating variants is not uniformly reported, the evidence collectively suggests familial clustering that supports a recessive mode of inheritance (PMID:23430875).

Functional studies provide moderate experimental evidence supporting a pathogenic role for COG5 deficiency. In patient-derived cells, reduced expression of COG5 was observed, and rescue experiments using wild-type cDNA restored normal Golgi-to-endoplasmic reticulum trafficking. Furthermore, in vitro co-immunoprecipitation studies demonstrated that pathogenic variants disrupt the interaction between COG5 and its binding partner COG7, thereby perturbing Golgi function (PMID:38987656). These functional assays align with the genetic findings and underscore the mechanistic basis of the disorder.

The genetic and functional evidence converge to support a strong ClinGen classification for the association between COG5 and congenital disorders of glycosylation. Multiple independent case reports and segregation analyses, along with corroborative functional rescue experiments, provide comprehensive support for the pathogenicity of COG5 mutations in this condition. The accumulation of evidence from multi‐patient studies further reinforces the clinical relevance of these findings (PMID:23228021).

In conclusion, the synthesis of genetic and experimental data establishes a robust, clinically meaningful association between COG5 and congenital disorders of glycosylation. This integrated evidence supports the use of COG5 sequencing as a critical component in the diagnostic evaluation of patients with suspected CDG. Key take‑home: Recognizing COG5 deficiency can offer significant guidance for early diagnosis, genetic counseling, and tailored therapeutic strategies.

References

• Human Molecular Genetics • 2009 • Deficiency in COG5 causes a moderate form of congenital disorders of glycosylation PMID:19690088
• JIMD Reports • 2012 • COG5-CDG with a Mild Neurohepatic Presentation PMID:23430875
• Frontiers in Genetics • 2020 • Identification of Two Novel Mutations in COG5 Causing Congenital Disorder of Glycosylation PMID:32174980
• Molecular Syndromology • 2023 • The First Congenital Disorders of Glycosylation Patient (Fetus) with Homozygous COG5 c.95T>G Variant PMID:37064333
• Orphanet Journal of Rare Diseases • 2012 • COG5-CDG: expanding the clinical spectrum PMID:23228021
• 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

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