title: Key features and clinical variability of COG6-CDG.
abstract: The conserved oligomeric Golgi (COG) complex consists of eight subunits and plays a crucial role in Golgi trafficking and positioning of glycosylation enzymes. Mutations in all COG subunits, except subunit 3, have been detected in patients with congenital disorders of glycosylation (CDG) of variable severity. So far, 3 families with a total of 10 individuals with biallelic COG6 mutations have been described, showing a broad clinical spectrum. Here we present 7 additional patients with 4 novel COG6 mutations. In spite of clinical variability, we delineate the core features of COG6-CDG i.e. liver involvement (9/10), microcephaly (8/10), developmental disability (8/10), recurrent infections (7/10), early lethality (6/10), and hypohidrosis predisposing for hyperthermia (6/10) and hyperkeratosis (4/10) as ectodermal signs. Regarding all COG6-related disorders a genotype-phenotype correlation can be discerned ranging from deep intronic mutations found in Shaheen syndrome as the mildest form to loss-of-function mutations leading to early lethal CDG phenotypes. A comparison with other COG deficiencies suggests ectodermal changes to be a hallmark of COG6-related disorders. Our findings aid clinical differentiation of this complex group of disorders and imply subtle functional differences between the COG complex subunits.
authors.affiliation: Center for Human Genetics, University of Leuven, Leuven, Belgium; Center for Metabolic Diseases, University Hospital Gasthuisberg, Leuven, Belgium.
authors.forename: Daisy
authors.initials: D
authors.lastname: Rymen
authors.affiliation: Neonatology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
authors.forename: Julia
authors.initials: J
authors.lastname: Winter
authors.affiliation: Department of Metabolic Diseases, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Peter M
authors.initials: PM
authors.lastname: Van Hasselt
authors.affiliation: Center for Metabolic Diseases, University Hospital Gasthuisberg, Leuven, Belgium.
authors.forename: Jaak
authors.initials: J
authors.lastname: Jaeken
authors.affiliation: Department of Pediatric Metabolism and Nutrition, Dr. Sami Ulus Maternity and Children Research and Training Hospital, Ankara, Turkey.
authors.forename: Cigdem
authors.initials: C
authors.lastname: Kasapkara
authors.affiliation: Department of Pediatric Nutrition and Metabolism, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
authors.forename: Gulden
authors.initials: G
authors.lastname: Gokçay
authors.affiliation: Department of Metabolic Diseases, Wilhelmina Children's Hospital, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Hanneke
authors.initials: H
authors.lastname: Haijes
authors.affiliation: University Children's Hospital Queen Fabiola, Brussels, Belgium.
authors.forename: Philippe
authors.initials: P
authors.lastname: Goyens
authors.affiliation: Division of Metabolism and Nutrition, Department of Pediatrics, Hacettepe University, Ankara, Turkey.
authors.forename: Aysegul
authors.initials: A
authors.lastname: Tokatli
authors.affiliation: Center for Child and Adolescent Medicine, Heidelberg, Germany.
authors.forename: Christian
authors.initials: C
authors.lastname: Thiel
authors.affiliation: Institute of Human Genetics, University Medical Center, Johannes Gutenberg University, Mainz, Germany.
authors.forename: Oliver
authors.initials: O
authors.lastname: Bartsch
authors.affiliation: Berlin-Brandenburg Center for Regenerative Therapies, Charité-Universitaetsmedizin Berlin, Berlin, Germany.
authors.forename: Jochen
authors.initials: J
authors.lastname: Hecht
authors.affiliation: Institute of Medical Genetics and Human Genetics, Charité-Universitaetsmedizin Berlin, Berlin, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Krawitz
authors.affiliation: Department of Medical Genetics, UMC Utrecht, Section Metabolic Diagnostics, Utrecht, The Netherlands.
authors.forename: Hubertus C M T
authors.initials: HC
authors.lastname: Prinsen
authors.affiliation: Neonatology, University Medical Center of the Johannes Gutenberg University Mainz, Mainz, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Mildenberger
authors.affiliation: Center for Human Genetics, University of Leuven, Leuven, Belgium.
authors.forename: Gert
authors.initials: G
authors.lastname: Matthijs
authors.affiliation: Berlin-Brandenburg Center for Regenerative Therapies, Charité-Universitaetsmedizin Berlin, Berlin, Germany; Institute of Medical Genetics and Human Genetics, Charité-Universitaetsmedizin Berlin, Berlin, Germany; Max Planck Institute for Molecular Genetics, Berlin, Germany. Electronic address: uwe.kornak@charite.de.
authors.forename: Uwe
authors.initials: U
authors.lastname: Kornak
mesh_terms: D033942:Adaptor Proteins, Vesicular Transport / Q000235:genetics*; D000293:Adolescent; D002648:Child; D018981:Congenital Disorders of Glycosylation / Q000150:complications / Q000235:genetics* / Q000503:physiopathology*; D005260:Female; D056726:Genetic Association Studies; D006031:Glycosylation; D006056:Golgi Apparatus / Q000235:genetics* / Q000473:pathology; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D008297:Male; D008831:Microcephaly / Q000209:etiology; D008969:Molecular Sequence Data; D009154:Mutation; D010641:Phenotype; D055815:Young Adult
chemical_list: D033942:Adaptor Proteins, Vesicular Transport; C553748:COG6 protein, human
keywords: CDG; COG6; Congenital disorder of glycosylation; Conserved oligomeric Golgi complex