PIGG variant pathogenicity assessment reveals characteristic features within 19 families

  • Genet Med. 2021 Oct;23(10):1873-1881. doi: 10.1038/s41436-021-01215-9.
Camille Tremblay-Laganière  1 ,  Reza Maroofian  2 ,  Thi Tuyet Mai Nguyen  1 ,  Ehsan Ghayoor Karimiani  3  4 ,  Salman Kirmani  5 ,  Fizza Akbar  5 ,  Shahnaz Ibrahim  5 ,  Bushra Afroze  5 ,  Mohammad Doosti  4 ,  Farah Ashrafzadeh  6 ,  Meisam Babaei  7 ,  Stephanie Efthymiou  2 ,  Marilena Christoforou  2 ,  Tipu Sultan  8 ,  Roger L Ladda  9 ,  Heather M McLaughlin  10 ,  Rebecca Truty  10 ,  Sonal Mahida  11 ,  Julie S Cohen  11  12 ,  Kristin Baranano  11  12 ,  Fatima Y Ismail  12  13 ,  Millan S Patel  14 ,  Anna Lehman  14 ,  Andrew C Edmondson  15 ,  Amanda Nagy  16 ,  Melissa A Walker  16 ,  Saadet Mercimek-Andrews  17  18 ,  Yuta Maki  19  20 ,  Rani Sachdev  21  22 ,  Rebecca Macintosh  21 ,  Elizabeth E Palmer  21  22 ,  Grazia M S Mancini  23 ,  Tahsin Stefan Barakat  23 ,  Robert Steinfeld  24 ,  Christina T Rüsch  24 ,  Georg M Stettner  24 ,  Matias Wagner  25  26 ,  Saskia B Wortmann  27  28 ,  Usha Kini  29 ,  Angela F Brady  30 ,  Karen L Stals  31 ,  Naila Ismayilova  32 ,  Sian Ellard  31  33 ,  Danilo Bernardo  34 ,  Kimberly Nugent  35 ,  Scott D McLean  35 ,  Stylianos E Antonarakis  36 ,  Henry Houlden  2 ,  Taroh Kinoshita  37  38 ,  Philippe M Campeau  39 ,  Yoshiko Murakami  40  41
Affiliations
  • 1. Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine and University of Montreal, Montreal, QC, Canada.
  • 2. Department of Neuromuscular Diseases, UCL Queen Square Institute of Neurology and The National Hospital for Neurology and Neurosurgery, London, UK.
  • 3. Genetics Research Centre, Molecular and Clinical Sciences Institute, St. George's Hospital, University of London, London, UK.
  • 4. Next Generation Genetic Polyclinic, Mashhad, Iran.
  • 5. Department of Pediatrics & Child Health, Aga Khan University, Karachi, Pakistan.
  • 6. Department of Pediatric Neurology, Mashhad University of Medical Sciences, Mashhad, Iran.
  • 7. Department of Pediatrics, North Khorasan University of Medical Sciences, Bojnurd, Iran.
  • 8. Department of Pediatric Neurology, Institute of Child Health, The Children's Hospital Lahore, Lahore, Pakistan.
  • 9. Department of Pediatrics, Milton S Hershey Medical Centre, Hershey, PA, USA.
  • 10. Invitae Corporation, San Francisco, CA, USA.
  • 11. Division of Neurogenetics, Kennedy Krieger Institute, Baltimore, MD, USA.
  • 12. Department of Neurology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
  • 13. Department of Pediatrics, United Arab Emirates University, Al Ain, UAE.
  • 14. Department of Medical Genetics, University of British Columbia, Vancouver, BC, Canada.
  • 15. Division of Human Genetics, Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, PA, USA.
  • 16. Department of Neurology, Massachusetts General Hospital, Boston, MA, USA.
  • 17. Division of Clinical and Metabolic Genetics, Department of Pediatrics, University of Toronto, The Hospital for Sick Children, Toronto, ON, Canada.
  • 18. Department of Medical Genetics, Faculty of Medicine & Dentistry, University of Alberta, Stollery Children's Hospital, Alberta Health Services, Edmonton, AB, Canada.
  • 19. Department of Chemistry, Graduate School of Science, Osaka University, Toyonaka, Osaka, Japan.
  • 20. Project Research Center for Fundamental Sciences, Graduate School of Science, Osaka University, Toyonaka, Osaka, Japan.
  • 21. Sydney Children's Hospital, Centre for Clinical Genetics, Sydney Children's Hospital, High St, Randwick, UK.
  • 22. School of Women's and Children's Health, University of New South Wales, High St, Randwick, UK.
  • 23. Department of Clinical Genetics, Erasmus MC University Medical Center, Rotterdam, The Netherlands, CA, Rotterdam, The Netherlands.
  • 24. Department of Pediatric Neurology, University Children's Hospital Zurich, University of Zurich, Zurich, Switzerland.
  • 25. Institute of Human Genetics, School of Medicine, Technical University Munich, Munich, Germany.
  • 26. Institute for Neurogenomics Helmholtz Zentrum München, Neuherberg, Germany.
  • 27. University Children's Hospital, Paracelsus Medical School, Salzburg, Austria.
  • 28. Amalias Children's Hospital, RadboudUMC, Nijmegen, the Netherlands.
  • 29. Oxford Centre for Genomic Medicine, Oxford University Hospitals NHS Trust, Oxford, UK.
  • 30. North West Thames Regional Genetics Service, London North West University Healthcare NHS Trust, Northwick Park Hospital, Harrow, UK.
  • 31. Exeter Genomics Laboratory, Royal Devon and Exeter NHS Foundation Trust, Exeter, UK.
  • 32. Department of Paediatric Neurology, Chelsea and Westminster Hospital, London, UK.
  • 33. Institute of Biomedical and Clinical Science, College of Medicine and Health, University of Exeter, Exeter, UK.
  • 34. University of California San Francisco, Clinical Neurology, San Francisco, CA, UK.
  • 35. Department of Pediatrics, Baylor College of Medicine, The Children's Hospital of San Antonio, San Antonio, TX, USA.
  • 36. Department of Genetic Medicine and Development, University of Geneva Medical School, Geneva, Switzerland.
  • 37. Yabumoto Department of Intractable Disease Research, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan.
  • 38. Department of Immunoglycobiology, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan.
  • 39. Department of Pediatrics, Centre Hospitalier Universitaire Sainte-Justine and University of Montreal, Montreal, QC, Canada. [email protected].
  • 40. Yabumoto Department of Intractable Disease Research, Research Institute for Microbial Diseases, Osaka University, Suita, Osaka, Japan. [email protected].
  • 41. Department of Immunoglycobiology, World Premier International Immunology Frontier Research Center, Osaka University, Osaka, Japan. [email protected].
PMID: 34113002 DOI: 10.1038/s41436-021-01215-9
Abstract

Purpose: Phosphatidylinositol Glycan Anchor Biosynthesis, class G (PIGG) is an ethanolamine phosphate transferase catalyzing the modification of glycosylphosphatidylinositol (GPI). GPI serves as an anchor on the cell membrane for surface proteins called GPI-anchored proteins (GPI-APs). Pathogenic variants in genes involved in the biosynthesis of GPI cause inherited GPI deficiency (IGD), which still needs to be further characterized.

Methods: We describe 22 individuals from 19 unrelated families with biallelic variants in PIGG. We analyzed GPI-AP surface levels on granulocytes and fibroblasts for three and two individuals, respectively. We demonstrated enzymatic activity defects for PIGG variants in vitro in a PIGG/PIGO double knockout system.

Results: Phenotypic analysis of reported individuals reveals shared PIGG deficiency-associated features. All tested GPI-APs were unchanged on granulocytes whereas CD73 level in fibroblasts was decreased. In addition to classic IGD symptoms such as hypotonia, intellectual disability/developmental delay (ID/DD), and seizures, individuals with PIGG variants of null or severely decreased activity showed cerebellar atrophy, various neurological manifestations, and mitochondrial dysfunction, a feature increasingly recognized in IGDs. Individuals with mildly decreased activity showed autism spectrum disorder.

Conclusion: This in vitro system is a useful method to validate the pathogenicity of variants in PIGG and to study PIGG physiological functions.