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

J Inherit Metab Dis. 2020 Nov;43(6):1321-1332. doi: 10.1002/jimd.12278.

Devon L Johnstone ¹, Thi Tuyet Mai Nguyen ², Jessica Zambonin ¹ ³, Kristin D Kernohan ¹ ⁴, Anik St-Denis ², Nissan V Baratang ², Taila Hartley ¹, Michael T Geraghty ⁴, Julie Richer ³, Jacek Majewski ⁵ ⁶, Eric Bareke ⁵ ⁶, Andrea Guerin ⁷, Manuela Pendziwiat ⁸, Loren D M Pena ⁹ ¹⁰, Hilde M H Braakman ¹¹ ¹², Karen W Gripp ¹³, Andrew C Edmondson ¹⁴, Miao He ¹⁵, Rebecca C Spillmann ¹⁶, Erik A Eklund ¹⁷, Allan Bayat ¹⁸ ¹⁹, Hugh J McMillan ²⁰, Kym M Boycott ¹ ³, Philippe M Campeau ² ²¹

Affiliations

1 Children's Hospital of Eastern Ontario Research Institute, Ottawa, Ontario, Canada.
2 Research Center, CHU Sainte Justine, University of Montreal, Montreal, Quebec, Canada.
3 Department of Genetics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
4 Division of Metabolics and Newborn Screening, Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
5 Department of Human Genetics, McGill University, Montreal, Quebec, Canada.
6 McGill University and Genome Quebec Innovation Centre, Montreal, Quebec, Canada.
7 Division of Medical Genetics, Department of Pediatrics, Queen's University, Kingston, Ontario, Canada.
8 Department of Neuropediatrics, Christian-Albrechts-University of Kiel, Kiel, Germany.
9 Division of Human Genetics, Cincinnati Children's Hospital Medical Center, Cincinnati, Ohio, USA.
10 Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, Ohio, USA.
11 Department of Neurology, Academic Center for Epileptology Kempenhaeghe & Maastricht University Medical Center, Heeze, The Netherlands.
12 Department of Pediatric Neurology, Amalia Children's Hospital, Radboud University Medical Center & Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands.
13 Division of Medical Genetics, A. I. DuPont Hospital for Children/Nemours, Wilmington, Delaware, USA.
14 Department of Pediatrics, Division of Human Genetics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
15 Department of Pathology and Laboratory Medicine, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania, USA.
16 Division of Medical Genetics, Department of Pediatrics, Duke University Medical Center, Durham, North Carolina, USA.
17 Department of Pediatric Neurology, Region Skåne and Clinical Sciences, Lund University Skåne University Hospital (SUS), Lund, Sweden.
18 Department of Genetics and Personalized Medicine, Danish Epilepsy Centre, Dianalund, Denmark.
19 Institute for Regional Health Services Research, University of Southern Denmark, Odense, Denmark.
20 Division of Neurology, Department of Pediatrics, Children's Hospital of Eastern Ontario, Ottawa, Ontario, Canada.
21 Department of Pediatrics, Sainte-Justine Hospital, University of Montreal, Montreal, Quebec, Canada.

PMID: 32588908 DOI: 10.1002/jimd.12278

Abstract

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 biallelic PIGQ variants 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 wildtype PIGQ cDNA into patient fibroblasts rescued this phenotype. We expand the phenotypic spectrum of PIGQ-related disease and provide the first functional evidence in human cells of defective GPI-anchoring due to pathogenic variants in PIGQ.

Keywords

GPI; IGD; PIGQ; epileptic encephalopathy; exome sequencing; rare diseases.

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