COG6‐CDG: Novel variants and novel malformation

Abstract

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.

The SwedishCOG6‐CDGexperience and a comprehensive literature review

“… Note : Features of the two COG6‐CDG patients in our cohort (P1 and P2) and the previously published cases (R1:1, Cirnigliaro et al 6 ; R2:1, Ververi et al 7 ; R3:1, Zhao et al 8 ; R4:1, Lugli et al 10 ; R5:1, Lugli et al 9 ; R6:1, R6:2, Komlosi et al 11 ; R7:1, R7:2, Mandel et al 12 ; R8:1, Li et al 13 ; R9:1, Althonaian et al 14 ; R10:1, Wu et al 15 ; R11:1‐R11:7, Alsubhi et al 16 ; R12:1; Pérez‐Cerdá et al 17 ; R13:1‐R13:7, Rymen et al 18 ; R14:1, Shaheen et al 19 ; R15:1, Huybrechts et al 20 ; R16:1, Lubbehusen et al 21 In Shaheen et al, 19 11 more patients are mentioned but not individually clinically described). Abbreviations: ALT, alanine aminotransferase; aPTT, activated partial thromboplastin time; ASD, atrial septal defect; AST, aspartate aminotransferase; AV, aortic valve; BRP, birth‐related problems; CK, creatine kinase; DD, developmental delay; ep, epicanthal; F, female; FTT, failure to thrive; FXI, factor 11; HLH, hemophagocytic lymphohistiocytosis; ID, intellectual disability; IN, inverted nipples; LSE, low‐set ears; M, male; P, percentile; PDA, persistent ductus arteriosus; PFO, persistent foramen ovale; PT, prothrombin time; PVL, periventricular leukomalacia; SD, standard deviation; trc, thrombocytes; US, ultrasound; VSD, ventricular septal defect; WM, white matter; ‐, not present; +, present, N/R, not reported.…”

“… Note : Features of the two COG6‐CDG patients in our cohort (P1 and P2) and the previously published cases (R1:1, Cirnigliaro et al 6 ; R2:1, Ververi et al 7 ; R3:1, Zhao et al 8 ; R4:1, Lugli et al 10 ; R5:1, Lugli et al 9 ; R6:1, R6:2, Komlosi et al 11 ; R7:1, R7:2, Mandel et al 12 ; R8:1, Li et al 13 ; R9:1, Althonaian et al 14 ; R10:1, Wu et al 15 ; R11:1‐R11:7, Alsubhi et al 16 ; R12:1; Pérez‐Cerdá et al 17 ; R13:1‐R13:7, Rymen et al 18 ; R14:1, Shaheen et al 19 ; R15:1, Huybrechts et al 20 ; R16:1, Lubbehusen et al 21 In Shaheen et al, 19 11 more patients are mentioned but not individually clinically described). …”

“… 5 There are 16 publications totaling 41 patients with COG6‐CDG, of which 30 have clinical descriptions and 16 derive from two families (12 + 4). 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 Of the 41, only 9 presented with compound heterozygous variants, whereas the others were homozygous. The phenotype of COG6‐CDG varies between subjects, but is severe in a significant proportion with growth retardation, microcephaly, DD or ID, hypohidrosis, arthrogryposis, and 17/41 fatalities during the first 15 months of life.…”

N‐glycoproteomics reveals distinct glycosylation alterations in NGLY1‐deficient patient‐derived dermal fibroblasts

“…Congenital disorders of glycosylation (CDG) are genetic disorders that arise due to a defect in the synthesis of oligosaccharides, failure to add glycans onto the proteins/lipids, or defective maturation of glycoproteins and glycolipids in the cells 1 . CDG are monogenic disorders with predominant autosomal inheritance, besides autosomal and X‐linked inheritance 1,2 . Broadly, the CDG are classified into four groups—N‐linked glycosylation, O‐linked glycosylation, combined N‐ and O‐linked glycosylation, and glycosylphosphatidylinositol anchor and glycolipid biosynthesis defects 1,3 …”

“…1 CDG are monogenic disorders with predominant autosomal inheritance, besides autosomal and X-linked inheritance. 1,2 Broadly, the CDG are classified into four groups-N-linked glycosylation, O-linked glycosylation, combined N-and O-linked glycosylation, and glycosylphosphatidylinositol anchor and glycolipid biosynthesis defects. 1,3 More than 160 different types of CDG have been described to date.…”