COG7 – COG7-congenital disorder of glycosylation type IIe

Congenital disorder of glycosylation type IIe is an autosomal recessive multisystem disease caused by biallelic pathogenic variants in COG7, a subunit of the conserved oligomeric Golgi (COG) complex essential for N- and O-glycan processing. Patients present early in life with neurodevelopmental impairment and systemic involvement reflecting defective vesicular trafficking.

Three probands across two consanguineous families ([PMID:17356545]) and two previously described unrelated patients ([PMID:17356545]) are homozygous for the same intronic splice-site variant c.169+4A>C. This variant segregates with disease in affected siblings and is absent from control databases. The recurrence of a single splice variant in multiple families establishes a consistent autosomal recessive inheritance pattern.

Affected individuals uniformly exhibit severe progressive microcephaly, hypotonia, adducted thumbs, feeding difficulties with failure to thrive, growth retardation, wrinkled skin, cardiac anomalies including ventricular septal defect, and episodic hyperthermia. These features align with HPO terms for hypotonia (HP:0001252), growth delay (HP:0001510), premature skin wrinkling (HP:0100678), failure to thrive (HP:0001508), and abnormal heart morphology (HP:0001627).

Functional assays on patient fibroblasts demonstrate combined N- and O-linked glycosylation defects with hyposialylation, and Western blot analysis reveals a severe reduction of both COG7 and COG5 subunits, confirming loss of COG7 function. These data establish a loss-of-function mechanism consistent with clinical manifestations.

No conflicting evidence has been reported. Given the reproducible genotype–phenotype correlation, consistent segregation, and concordant biochemical defects, COG7 meets ClinGen criteria for a "Moderate" gene–disease association. Clinical testing for c.169+4A>C and glycosylation studies are recommended for patients with progressive microcephaly, neurodevelopmental delay, and the described multisystem features.

Key Take-Home: Biallelic COG7 c.169+4A>C causes a consistent autosomal recessive CDG IIe phenotype, and targeted genetic and glycosylation assays enable definitive diagnosis.

References

• European Journal of Human Genetics | 2007 | A common mutation in the COG7 gene with a consistent phenotype including microcephaly, adducted thumbs, growth retardation, VSD and episodes of hyperthermia. PMID:17356545

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