TY - JOUR
T1 - Gene identification in the congenital disorders of glycosylation type i by whole-exome sequencing
AU - Timal, Sharita
AU - Hoischen, Alexander
AU - Lehle, Ludwig
AU - Adamowicz, Maciej
AU - Huijben, Karin
AU - Sykut-cegielska, Jolanta
AU - Paprocka, Justyna
AU - Jamroz, Ewa
AU - Van spronsen, Francjan J.
AU - Körner, Christian
AU - Gilissen, Christian
AU - Rodenburg, Richard J.
AU - Eidhof, Ilse
AU - Van den heuvel, Lambert
AU - Thiel, Christian
AU - Wevers, Ron A.
AU - Morava, Eva
AU - Veltman, Joris
AU - Lefeber, Dirk J.
N1 - Funding Information:
This work was financially supported by the Institute of Genetic and Metabolic Disease (IGMD) (grant to D.J.L., R.J.R. and J.V.) and by the Körber-Stiftung to L.L.
PY - 2012/10
Y1 - 2012/10
N2 - 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.
AB - 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.
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U2 - 10.1093/hmg/dds123
DO - 10.1093/hmg/dds123
M3 - Article
C2 - 22492991
AN - SCOPUS:84866425378
SN - 0964-6906
VL - 21
SP - 4151
EP - 4161
JO - Human molecular genetics
JF - Human molecular genetics
IS - 19
M1 - dds123
ER -