Bi-allelic Variants in the GPI Transamidase Subunit PIGK Cause a Neurodevelopmental Syndrome with Hypotonia, Cerebellar Atrophy, and Epilepsy: American Journal of Human Genetics

T.T.M. Nguyen, Y. Murakami, S. Mobilio, M. Niceta, G. Zampino, C. Philippe, S. Moutton, M.S. Zaki, K.N. James, D. Musaev, W. Mu, K. Baranano, J.R. Nance, J.A. Rosenfeld, N. Braverman, A. Ciolfi, F. Millan, R.E. Person, A.-L. Bruel, C. Thauvin-RobinetA. Ververi, C. DeVile, A. Male, S. Efthymiou, R. Maroofian, H. Houlden, S. Maqbool, F. Rahman, N.V. Baratang, J. Rousseau, A. St-Denis, M.J. Elrick, I. Anselm, L.H. Rodan, M. Tartaglia, J. Gleeson, T. Kinoshita, P.M. Campeau

Research output: Contribution to journalArticlepeer-review


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. © 2020 American Society of Human Genetics
Original languageEnglish
Pages (from-to)484-495
Number of pages12
JournalAm. J. Hum. Genet.
Issue number4
Publication statusPublished - 2020


  • glycosylphosphatidylinositol (GPI)
  • GPI8
  • inherited GPI deficiency disorders (IGDs)
  • PIGK
  • transamidase
  • alkaline phosphatase
  • glycosylphosphatidylinositol
  • acyltransferase
  • cell adhesion molecule
  • COOH-terminal signal transamidase
  • PIGK protein, human
  • alkaline phosphatase blood level
  • allele
  • animal cell
  • Article
  • blood sampling
  • cell surface
  • cerebellar ataxia
  • cerebellum atrophy
  • child
  • clinical article
  • clinical feature
  • cohort analysis
  • controlled study
  • developmental delay
  • differential diagnosis
  • disease association
  • enzyme subunit
  • epilepsy
  • exome
  • face dysmorphia
  • fibroblast
  • flow cytometry
  • fluorescence activated cell sorting
  • gene
  • gene identification
  • gene overexpression
  • gene sequence
  • genetic conservation
  • genetic transfection
  • genetic variability
  • human
  • human cell
  • in vitro study
  • intellectual impairment
  • loss of function mutation
  • muscle hypotonia
  • neuropathology
  • nonhuman
  • nuclear magnetic resonance imaging
  • PIGK gene
  • preschool child
  • priority journal
  • cerebellum disease
  • female
  • genetic variation
  • genetics
  • male
  • mental disease
  • multiple malformation syndrome
  • nervous system malformation
  • pedigree
  • syndrome
  • Abnormalities, Multiple
  • Acyltransferases
  • Alleles
  • Cell Adhesion Molecules
  • Cerebellar Diseases
  • Epilepsy
  • Female
  • Genetic Variation
  • Humans
  • Intellectual Disability
  • Male
  • Muscle Hypotonia
  • Nervous System Malformations
  • Neurodevelopmental Disorders
  • Pedigree
  • Syndrome


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