COG6-CDG: Novel variants and novel malformation

Birth Defects Res. 2022 Mar;114(5-6):165-174. doi: 10.1002/bdr2.1981. Epub 2022 Jan 23.


Background: Deficiency of Conserved Oligomeric Golgi (COG) subunits (COG1-8) is characterized by both N- and O-protein glycosylation defects associated with destabilization and mislocalization of Golgi glycosylation machinery components (COG-CDG). Patients with COG defects present with neurological and multisystem involvement and possible malformation occurrence. Eighteen patients with COG6-CDG (COG6 mutations) were reported to date. We describe a patient with COG6-CDG with novel variants and a novel clinical feature namely a congenital recto-vaginal fistula.

Methods: In-depth serum N- and O-glycosylation structural analyses were conducted by MALDI-TOF mass spectrometry. COG6 variants were identified by a gene panel and confirmed by Sanger sequencing.

Results: This female newborn presented with facial dysmorphism, distal arthrogryposis and recurrent stool discharges per vaginam. A double-contrast barium-enema X-ray study revealed a dehiscence (approximately 5 mm) at the anterior wall of the rectal ampoule communicating with the vagina consistent with a recto-vaginal fistula. She had developmental delay, corpus callosum dysgenesis, liver and gastrointestinal involvement, hyperthermia episodes and early demise. Serum N- and O-glycosylation analyses pointed to a profound Golgi disarrangement. We identified two novel variants in COG6: a deletion of 1 bp mutation c.823delA creating a shift in the reading frame and a premature stop codon and a 3 bp deletion (c.1141_1143delCTC) producing an in-frame deletion of 1 amino acid.

Conclusion: The congenital recto-vaginal fistula is a rare type of anorectal malformation that, to our knowledge, has not been reported in patients with a COG6 defect nor in patients with other COG defects. This study broadens COG6-CDG genetic landscape and spectrum of malformations.

Keywords: COG6; combined N- and O-glycosylation defect; congenital ano-rectal malformations; congenital disorder of glycosylation (CDG); corpus callosum dysgenesis.

Publication types

  • Case Reports

MeSH terms

  • Adaptor Proteins, Vesicular Transport / genetics
  • Adaptor Proteins, Vesicular Transport / metabolism
  • Congenital Disorders of Glycosylation* / complications
  • Congenital Disorders of Glycosylation* / genetics
  • Congenital Disorders of Glycosylation* / metabolism
  • Female
  • Glycosylation
  • Golgi Apparatus / genetics
  • Golgi Apparatus / metabolism
  • Humans
  • Infant, Newborn
  • Vaginal Fistula* / complications


  • Adaptor Proteins, Vesicular Transport
  • COG6 protein, human