Early infantile epileptic encephalopathy due to biallelic pathogenic variants inPIGQ: Report of seven new subjects and review of the literature

Devon L. Johnstone, Thi Tuyet Mai Nguyen, Jessica Zambonin, Kristin D. Kernohan, Anik St-Denis, Nissan V. Baratang, Taila Hartley, Michael T. Geraghty, Julie Richer, Jacek Majewski, Eric Bareke, Andrea Guerin, Manuela Pendziwiat, Loren D. M. Pena, Hilde M. H. Braakman, Karen W. Gripp, Andrew C. Edmondson, Miao He, Rebecca C. Spillmann, Erik A. EklundAllan Bayat, Hugh J. McMillan, Kym M. Boycott*, Philippe M. Campeau*

*Corresponding author for this work

Research output: Contribution to journal(Systematic) Review article peer-review

8 Citations (Web of Science)


We investigated seven children from six families to expand the phenotypic spectrum associated with an early infantile epileptic encephalopathy caused by biallelic pathogenic variants in the phosphatidylinositol glycan anchor biosynthesis class Q (PIGQ) gene. The affected children were all identified by clinical or research exome sequencing. Clinical data, including EEGs and MRIs, was comprehensively reviewed and flow cytometry and transfection experiments were performed to investigate PIGQ function. Pathogenic biallelicPIGQvariants were associated with increased mortality. Epileptic seizures, axial hypotonia, developmental delay and multiple congenital anomalies were consistently observed. Seizure onset occurred between 2.5 months and 7 months of age and varied from treatable seizures to recurrent episodes of status epilepticus. Gastrointestinal issues were common and severe, two affected individuals had midgut volvulus requiring surgical correction. Cardiac anomalies including arrythmias were observed. Flow cytometry using granulocytes and fibroblasts from affected individuals showed reduced expression of glycosylphosphatidylinositol (GPI)-anchored proteins. Transfection of wildtypePIGQcDNA into patient fibroblasts rescued this phenotype. We expand the phenotypic spectrum ofPIGQ-related disease and provide the first functional evidence in human cells of defective GPI-anchoring due to pathogenic variants inPIGQ.

Original languageEnglish
Pages (from-to)1321-1332
Number of pages12
JournalJournal of Inherited Metabolic Disease
Issue number6
Early online date3 Aug 2020
Publication statusPublished - Nov 2020


  • epileptic encephalopathy
  • exome sequencing
  • GPI
  • IGD
  • PIGQ
  • rare diseases
  • 1ST STEP
  • GENE

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