2. Academic Validation
  3. Bi-allelic Variants in the GPI Transamidase Subunit PIGK Cause a Neurodevelopmental Syndrome with Hypotonia, Cerebellar Atrophy, and Epilepsy

Bi-allelic Variants in the GPI Transamidase Subunit PIGK Cause a Neurodevelopmental Syndrome with Hypotonia, Cerebellar Atrophy, and Epilepsy

  • Am J Hum Genet. 2020 Apr 2;106(4):484-495. doi: 10.1016/j.ajhg.2020.03.001.
Thi Tuyet Mai Nguyen 1,  Yoshiko Murakami 2,  Sabrina Mobilio 3,  Marcello Niceta 4,  Giuseppe Zampino 5,  Christophe Philippe 6,  Sébastien Moutton 7,  Maha S Zaki 8,  Kiely N James 9,  Damir Musaev 9,  Weiyi Mu 10,  Kristin Baranano 11,  Jessica R Nance 11,  Jill A Rosenfeld 12,  Nancy Braverman 13,  Andrea Ciolfi 4,  Francisca Millan 14,  Richard E Person 14,  Ange-Line Bruel 15,  Christel Thauvin-Robinet 16,  Athina Ververi 17,  Catherine DeVile 18,  Alison Male 17,  Stephanie Efthymiou 19,  Reza Maroofian 19,  Henry Houlden 19,  Shazia Maqbool 20,  Fatima Rahman 20,  Nissan V Baratang 1,  Justine Rousseau 1,  Anik St-Denis 1,  Matthew J Elrick 11,  Irina Anselm 21,  Lance H Rodan 22,  Marco Tartaglia 4,  Joseph Gleeson 9,  Taroh Kinoshita 2,  Philippe M Campeau 23
Affiliations

Affiliations

  • 1 CHU-Sainte Justine Research Center, University of Montreal, Montreal, QC, Canada, H3T1C5.
  • 2 Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
  • 3 Division of Medical Genetics, Northwell Health, Manhasset, NY 11030, USA.
  • 4 Genetics and Rare Diseases Research Division, Ospedale Pediatrico Bambino Gesù, IRCCS, 00146 Rome, Italy.
  • 5 Center for Rare Disease and Congenital Defects, Fondazione Policlinico Universitario A. Gemelli, Università Cattolica del Sacro Cuore, 00168 Rome, Italy.
  • 6 UF Innovation en diagnostic génomique des maladies rares, CHU Dijon Bourgogne, and INSERM UMR1231 GAD, F-21000, Dijon, France.
  • 7 Reference Center for Developmental Anomalies, Department of Medical Genetics, Dijon University Hospital, Dijon, France.
  • 8 Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo 12311, Egypt.
  • 9 Laboratory for Pediatric Brain Disease, Howard Hughes Medical Institute, University of California, San Diego, La Jolla, CA 92093, USA; Rady Children's Institute for Genomic Medicine, Rady Children's Hospital, San Diego, CA 92123, USA.
  • 10 Institute of Genetic Medicine, Johns Hopkins University, Baltimore MD, USA.
  • 11 Department of Neurology, Johns Hopkins School of Medicine, Baltimore, MD, 21287 USA.
  • 12 Baylor College of Medicine, Houston, TX 77030, USA.
  • 13 Department of Human Genetics, McGill University and Montreal Children's Hospital, Montreal, QC, Canada, H4A 3J1.
  • 14 GeneDx, Gaithersburg, MD 20877, USA.
  • 15 UF Innovation en diagnostic génomique des maladies rares, CHU Dijon Bourgogne, Dijon, France.
  • 16 Centre de référence maladies rares-Déficiences Intellectuelles de causes rares, Centre de génétique, Hôpital d'Enfants, UF Innovation en diagnostic génomique des maladies rares, CHU Dijon Bourgogne, Dijon.
  • 17 Clinical Genetic Service, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street, London, WC1N 3JH, UK.
  • 18 Department of Neurology, Great Ormond Street Hospital for Children NHS Foundation Trust, Great Ormond Street, London, WC1N 3JH, UK.
  • 19 Department of Neuromuscular Disorders, UCL Institute of Neurology, London WC1N 3BG, UK.
  • 20 Development and Behavioural Pediatrics Department, Institute of Child Health and The Children Hospital, Lahore, Pakistan.
  • 21 Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • 22 Division of Genetics and Genomics and Department of Neurology, Boston Children's Hospital, Harvard Medical School, Boston, MA 02115, USA.
  • 23 CHU-Sainte Justine Research Center, University of Montreal, Montreal, QC, Canada, H3T1C5; Department of Pediatrics, University of Montreal, Montreal, QC, Canada, H3T1C5. Electronic address: p.campeau@umontreal.ca.
PMID: 32220290 DOI: 10.1016/j.ajhg.2020.03.001
Abstract

Glycosylphosphatidylinositol (GPI)-anchored proteins are critical for embryogenesis, neurogenesis, and cell signaling. Variants in several genes participating in GPI biosynthesis and processing lead to decreased cell surface presence of GPI-anchored proteins (GPI-APs) and cause inherited GPI deficiency disorders (IGDs). In this report, we describe 12 individuals from nine unrelated families with 10 different bi-allelic PIGK variants. PIGK encodes a component of the GPI transamidase complex, which attaches the GPI anchor to proteins. Clinical features found in most individuals include global developmental delay and/or intellectual disability, hypotonia, cerebellar ataxia, cerebellar atrophy, and facial dysmorphisms. The majority of the individuals have epilepsy. Two individuals have slightly decreased levels of serum Alkaline Phosphatase, while eight do not. Flow cytometric analysis of blood and fibroblasts from affected individuals showed decreased cell surface presence of GPI-APs. The overexpression of wild-type (WT) PIGK in fibroblasts rescued the levels of cell surface GPI-APs. In a knockout cell line, transfection with WT PIGK also rescued the GPI-AP levels, but transfection with the two tested mutant variants did not. Our study not only expands the clinical and known genetic spectrum of IGDs, but it also expands the genetic differential diagnosis for cerebellar atrophy. Given the fact that cerebellar atrophy is seen in Other IGDs, flow cytometry for GPI-APs should be considered in the work-ups of individuals presenting this feature.

Keywords

GPI8; PIGK; glycosylphosphatidylinositol (GPI); inherited GPI deficiency disorders (IGDs); transamidase.

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