title: Gene identification in the congenital disorders of glycosylation type I by whole-exome sequencing.
abstract: Congenital disorders of glycosylation type I (CDG-I) form a growing group of recessive neurometabolic diseases. Identification of disease genes is compromised by the enormous heterogeneity in clinical symptoms and the large number of potential genes involved. Until now, gene identification included the sequential application of biochemical methods in blood samples and fibroblasts. In genetically unsolved cases, homozygosity mapping has been applied in consanguineous families. Altogether, this time-consuming diagnostic strategy led to the identification of defects in 17 different CDG-I genes. Here, we applied whole-exome sequencing (WES) in combination with the knowledge of the protein N-glycosylation pathway for gene identification in our remaining group of six unsolved CDG-I patients from unrelated non-consanguineous families. Exome variants were prioritized based on a list of 76 potential CDG-I candidate genes, leading to the rapid identification of one known and two novel CDG-I gene defects. These included the first X-linked CDG-I due to a de novo mutation in ALG13, and compound heterozygous mutations in DPAGT1, together the first two steps in dolichol-PP-glycan assembly, and mutations in PGM1 in two cases, involved in nucleotide sugar biosynthesis. The pathogenicity of the mutations was confirmed by showing the deficient activity of the corresponding enzymes in patient fibroblasts. Combined with these results, the gene defect has been identified in 98% of our CDG-I patients. Our results implicate the potential of WES to unravel disease genes in the CDG-I in newly diagnosed singleton families.
authors.affiliation: Department of Neurology, Institute for Genetic and Metabolic Disease, Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands.
authors.forename: Sharita
authors.initials: S
authors.lastname: Timal
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoischen
authors.forename: Ludwig
authors.initials: L
authors.lastname: Lehle
authors.forename: Maciej
authors.initials: M
authors.lastname: Adamowicz
authors.forename: Karin
authors.initials: K
authors.lastname: Huijben
authors.forename: Jolanta
authors.initials: J
authors.lastname: Sykut-Cegielska
authors.forename: Justyna
authors.initials: J
authors.lastname: Paprocka
authors.forename: Ewa
authors.initials: E
authors.lastname: Jamroz
authors.forename: Francjan J
authors.initials: FJ
authors.lastname: van Spronsen
authors.forename: Christian
authors.initials: C
authors.lastname: Körner
authors.forename: Christian
authors.initials: C
authors.lastname: Gilissen
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Rodenburg
authors.forename: Ilse
authors.initials: I
authors.lastname: Eidhof
authors.forename: Lambert
authors.initials: L
authors.lastname: Van den Heuvel
authors.forename: Christian
authors.initials: C
authors.lastname: Thiel
authors.forename: Ron A
authors.initials: RA
authors.lastname: Wevers
authors.forename: Eva
authors.initials: E
authors.lastname: Morava
authors.forename: Joris
authors.initials: J
authors.lastname: Veltman
authors.forename: Dirk J
authors.initials: DJ
authors.lastname: Lefeber
mesh_terms: D000293:Adolescent; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D018981:Congenital Disorders of Glycosylation / Q000235:genetics* / Q000378:metabolism; D059472:Exome; D005260:Female; D015894:Genome, Human; D006031:Glycosylation; D006801:Humans; D007223:Infant; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D010375:Pedigree; D011506:Proteins / Q000235:genetics / Q000378:metabolism; D017422:Sequence Analysis, DNA; D055815:Young Adult
chemical_list: D011506:Proteins