Gene identification in the congenital disorders of glycosylation type I by whole-exome sequencing
| Autor: | Justyna Paprocka, Eva Morava, Lambert P. van den Heuvel, Ron A. Wevers, Christian Thiel, Maciej Adamowicz, Ewa Jamroz, Joris A. Veltman, Richard J. Rodenburg, Sharitakoemari Timal, Christian Gilissen, Francjan J. van Spronsen, Karin Huijben, Jolanta Sykut-Cegielska, Ilse Eidhof, Ludwig Lehle, Alexander Hoischen, Christian Körner, Dirk Lefeber |
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| Přispěvatelé: | Faculteit Medische Wetenschappen/UMCG, Center for Liver, Digestive and Metabolic Diseases (CLDM) |
| Rok vydání: | 2012 |
| Předmět: |
Male
Candidate gene Glycosylation Aetiology screening and detection [ONCOL 5] Compound heterozygosity medicine.disease_cause SERUM Cohort Studies TRANSFERASE Congenital Disorders of Glycosylation Exome Child Genetics (clinical) Exome sequencing Genetics Mutation DPAGT1 General Medicine Disease gene identification Pedigree DEFICIENCY DOLICHOL Mitochondrial medicine [IGMD 8] Child Preschool Female STEPS ENZYMES congenital hereditary and neonatal diseases and abnormalities Adolescent Molecular Sequence Data Biology Genomic disorders and inherited multi-system disorders [IGMD 3] Young Adult medicine Humans YEAST BIOSYNTHESIS Glycostation disorders [DCN PAC - Perception action and control IGMD 4] Molecular Biology Gene DCN NN - Brain networks and neuronal communication Genome Human MUTATIONS Infant Proteins Sequence Analysis DNA Glycostation disorders [IGMD 4] CDG Genetics and epigenetic pathways of disease Genomic disorders and inherited multi-system disorders [NCMLS 6] |
| Zdroj: | Human Molecular Genetics, 21, 19, pp. 4151-61 Human Molecular Genetics, 21, 4151-61 Human Molecular Genetics, 21(19), 4151-4161. Oxford University Press |
| ISSN: | 0964-6906 |
| Popis: | Item does not contain fulltext 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. |
| Databáze: | OpenAIRE |
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