Deficiency of Subunit 6 of the Conserved Oligomeric Golgi Complex (COG6-CDG): Second Patient, Different Phenotype

Abstract

We describe a 27-month-old girl with COG6 deficiency. She is the first child of healthy consanguineous Moroccan parents. She presented at birth with dysmorphic features including microcephaly, post-axial polydactyly, broad palpebral fissures, retrognathia, and anal anteposition. The clinical phenotype was further characterised by multiorgan involvement including mild psychomotor retardation, and microcephaly, chronic inflammatory bowel disease, micronodular liver cirrhosis, associated with life-threatening and recurrent infections due to combined T- and B-cell dysfunction and neutrophil dysfunction.Mutation analysis showed the patient to be homozygous for the c.G1646T mutation in the COG6 gene. She is the second reported patient with a deficiency of subunit 6 of the COG complex. Although both patients are homozygous for the same mutation, they present a markedly different clinical picture. Indeed immunodeficiency as well as inflammatory bowel disease has not been described previously in patients with any COG-CDG.

Expanding the clinical phenotype of COG6 deficiency

“…This mutation is associated with a deficiency of the COG6 protein, as evidenced by RT-PCR results. However, unlike the majority of known cases of COG deficiency, including COG6-congenital disorders of glycosylation (CDG) reports,2 3 they did not find the characteristic transferrin iso-electric focusing (TIEF) type II pattern in their patients.…”

“…In support of pathogenicity, Glycine549 is a highly conserved amino acid residue from yeast to humans and the amino acid change is predicted to be damaging (using Polyphen), as is the amino acid change to valine. Meanwhile, the homozygous G549V mutation has been described by Huybrechts et al 2 who also described the characteristic type II TIEF pattern with abnormal apoCIII analysis indicative for a combined N- and O-glycosylation defect in their patient. The clinical findings in both patients described thus far align with biochemical proof by Lübbehusen et al ,3 showing that the decreased amount of COG6 protein was provoked by the instability of the mutated COG6-mRNA and not by degradation of the mutated protein.…”

Key features and clinical variability of COG6-CDG

“…Since this is a frequent minor birth defect it is currently unclear whether it is related to the COG6 defect. Indeed, in the family described by Huybrechts et al the healthy sibling displayed polydactyly [11].…”

“…Subsequently, also defects in COG1, -2, -4, -5, -6, and -8 have been identified in patients with a type 2 pattern upon IEF of serum transferrin [5][6][7][8][9]. Only 3 families with COG6-deficient patients have been described so far [10][11][12]. Of these patients two showed a CDG phenotype while the others, harboring a deep intronic splice site mutation, were characterized only by mild intellectual disability and ectodermal changes.…”

Congenital disorders of glycosylation: a concise chart of glycocalyx dysfunction

“…The most severe diseases are observed for COG6, COG7 and COG8 mutations, associated with severe neurological impairment, liver dysfunction, and infantile lethality [52][53][54][55]. The identification of milder cases of COG6 and COG7 deficiency harboring different mutations [56,57] however shows that the severity of the disease does not simply relate to the subunit affected but rather to the capability of forming a fully functional COG complex. Besides the severe diseases observed for COG6 and COG7 defects, moderate clinical manifestations have been associated with mutations in COG1 [58,59], COG2 [60], COG4 [61,62], and COG5 [63][64][65].…”