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

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

  • Hum Mutat. 2018 Jun;39(6):822-826. doi: 10.1002/humu.23420.
Alistair T Pagnamenta 1,  Yoshiko Murakami 2 3,  Consuelo Anzilotti 4,  Hannah Titheradge 5,  Adam J Oates 6,  Jenny Morton 5,  DDD Study 7,  Taroh Kinoshita 2 3,  Usha Kini 8,  Jenny C Taylor 1
Affiliations

Affiliations

  • 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.
PMID: 29573052 DOI: 10.1002/humu.23420
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.

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