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Eur J Hum Genet. 2017 Jun;25(6):669-679. doi: 10.1038/ejhg.2017.32. Epub 2017 Mar 22.

Analysis of exome data for 4293 trios suggests GPI-anchor biogenesis defects are a rare cause of developmental disorders.

Author information

National Institute for Health Research Oxford Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, UK.
Department of Immunoregulation, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan.
Oxford NHS Regional Molecular Genetics Laboratory, Oxford University Hospitals NHS Trust, Oxford, UK.
The Henry Wellcome Building for Molecular Physiology, University of Oxford, Oxford, UK.
Department of Clinical Genetics, Oxford University Hospitals NHS Trust, Oxford, UK.
Sheffield Children's Hospital, Western Bank, Sheffield, UK.
South West Thames Regional Genetics Service, St George's Healthcare NHS Foundation Trust, London, UK.
Human Genetics and Genomic Medicine, Faculty of Medicine, University of Southampton and Wessex Clinical Genetics Service, University Hospital NHS Trust, Princess Anne Hospital, Southampton, UK.
Department of Clinical Genetics, Great Ormond Street Hospital for Children NHS Trust, London, UK.
Department of Clinical Genetics, Nottingham University Hospitals NHS Trust, Nottingham, UK.
Manchester Centre for Genomic Medicine, Institute of Human Development, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK.


Over 150 different proteins attach to the plasma membrane using glycosylphosphatidylinositol (GPI) anchors. Mutations in 18 genes that encode components of GPI-anchor biogenesis result in a phenotypic spectrum that includes learning disability, epilepsy, microcephaly, congenital malformations and mild dysmorphic features. To determine the incidence of GPI-anchor defects, we analysed the exome data from 4293 parent-child trios recruited to the Deciphering Developmental Disorders (DDD) study. All probands recruited had a neurodevelopmental disorder. We searched for variants in 31 genes linked to GPI-anchor biogenesis and detected rare biallelic variants in PGAP3, PIGN, PIGT (n=2), PIGO and PIGL, providing a likely diagnosis for six families. In five families, the variants were in a compound heterozygous configuration while in a consanguineous Afghani kindred, a homozygous c.709G>C; p.(E237Q) variant in PIGT was identified within 10-12 Mb of autozygosity. Validation and segregation analysis was performed using Sanger sequencing. Across the six families, five siblings were available for testing and in all cases variants co-segregated consistent with them being causative. In four families, abnormal alkaline phosphatase results were observed in the direction expected. FACS analysis of knockout HEK293 cells that had been transfected with wild-type or mutant cDNA constructs demonstrated that the variants in PIGN, PIGT and PIGO all led to reduced activity. Splicing assays, performed using leucocyte RNA, showed that a c.336-2A>G variant in PIGL resulted in exon skipping and p.D113fs*2. Our results strengthen recently reported disease associations, suggest that defective GPI-anchor biogenesis may explain ~0.15% of individuals with developmental disorders and highlight the benefits of data sharing.

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