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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.

Author information

1
National Institute for Health Research Oxford Biomedical Research Centre, Wellcome Centre for Human Genetics, University of Oxford, Oxford, Oxfordshire, UK.
2
Yabumoto Department of Intractable Disease Research, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan.
3
World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan.
4
Weatherall Institute of Molecular Medicine, Radcliffe Department of Medicine, John Radcliffe Hospital, University of Oxford, Oxford, UK.
5
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.
6
Radiology Department, Birmingham Children's Hospital, Birmingham, UK.
7
Wellcome Trust Sanger Institute, Wellcome Genome Campus, Hinxton, Cambridge, UK.
8
Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Foundation Trust, Oxford, UK.

Abstract

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.

KEYWORDS:

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

PMID:
29573052
PMCID:
PMC6001798
DOI:
10.1002/humu.23420
[Indexed for MEDLINE]
Free PMC Article

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