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Hum Mutat. 2018 Jun;39(6):822-826. doi: 10.1002/humu.23420. Epub 2018 Mar 30.

A homozygous variant disrupting the PIGH start-codon is associated with developmental delay, epilepsy, and microcephaly.

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National Institute for Health Research Oxford Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, Oxford, Oxfordshire, UK.
Yabumoto Department of Intractable Disease Research, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan.
Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK.
West Midlands Regional Clinical Genetics Service and Birmingham Health Partners, Birmingham Women's and Children's NHS Foundation Trust, Birmingham Women's Hospital, Mindelsohn Way, Edgbaston, Birmingham, UK.
Radiology Department, Birmingham Children's Hospital, Birmingham, UK.
Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.
Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.


Defective glycosylphosphatidylinositol (GPI)-anchor biogenesis can cause a spectrum of predominantly neurological problems. For eight genes critical to this biological process, disease associations are not yet reported. Scanning exomes from 7,833 parent-child trios and 1,792 singletons from the DDD study for biallelic variants in this gene-set uncovered a rare PIGH variant in a boy with epilepsy, microcephaly, and behavioral difficulties. Although only 2/2 reads harbored this c.1A > T transversion, the presence of ∼25 Mb autozygosity at this locus implied homozygosity, which was confirmed using Sanger sequencing. A similarly-affected sister was also homozygous. FACS analysis of PIGH-deficient CHO cells indicated that cDNAs with c.1A > T could not efficiently restore expression of GPI-APs. Truncation of PIGH protein was consistent with the utilization of an in-frame start-site at codon 63. In summary, we describe siblings harboring a homozygous c.1A > T variant resulting in defective GPI-anchor biogenesis and highlight the importance of exploring low-coverage variants within autozygous regions.


GPI-anchor biogenesis; PIGH; developmental delay; exome; microcephaly; phosphatidylinositol N-acetylglucosaminyltransferase

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