title: The genotypic and phenotypic spectrum of PIGA deficiency.
abstract: BACKGROUND
  Phosphatidylinositol glycan biosynthesis class A protein (PIGA) is one of the enzymes involved in the biosynthesis of glycosylphosphatidylinositol (GPI) anchor proteins, which function as enzymes, adhesion molecules, complement regulators and co-receptors in signal transduction pathways. Until recently, only somatic PIGA mutations had been reported in patients with paroxysmal nocturnal hemoglobinuria (PNH), while germline mutations had not been observed, and were suspected to result in lethality. However, in just two years, whole exome sequencing (WES) analyses have identified germline PIGA mutations in male patients with XLIDD (X-linked intellectual developmental disorder) with a wide spectrum of clinical presentations.
  
  
  RESULTS
  Here, we report on a new missense PIGA germline mutation [g.15342986C>T (p.S330N)] identified via WES followed by Sanger sequencing, in a Chinese male infant presenting with developmental arrest, infantile spasms, a pattern of lesion distribution on brain MRI resembling that typical of maple syrup urine disease, contractures, dysmorphism, elevated alkaline phosphatase, mixed hearing loss (a combination of conductive and sensorineural), liver dysfunction, mitochondrial complex I and V deficiency, and therapy-responsive dyslipidemia with confirmed lipoprotein lipase deficiency. X-inactivation studies showed skewing in the clinically unaffected carrier mother, and CD109 surface expression in patient fibroblasts was 57% of that measured in controls; together these data support pathogenicity of this mutation. Furthermore, we review all reported germline PIGA mutations (1 nonsense, 1 frameshift, 1 in-frame deletion, five missense) in 8 unrelated families.
  
  
  CONCLUSIONS
  Our case further delineates the heterogeneous phenotype of this condition for which we propose the term 'PIGA deficiency'. While the phenotypic spectrum is wide, it could be classified into two types (severe and less severe) with shared hallmarks of infantile spasms with hypsarrhythmia on EEG and profound XLIDD. In severe PIGA deficiency, as described in our patient, patients also present with dysmorphic facial features, multiple CNS abnormalities, such as thin corpus callosum and delayed myelination, as well as hypotonia and elevated alkaline phosphatase along with liver, renal, and cardiac involvement; its course is often fatal. The less severe form of PIGA deficiency does not involve facial dysmorphism and multiple CNS abnormalities; instead, patients present with milder IDD, treatable seizures and generally a longer lifespan.
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Vancouver, Canada. maja@cmmt.ubc.ca.|Department of Medical Genetics, University of British Columbia, Vancouver, Canada. maja@cmmt.ubc.ca.|Treatable Intellectual Disability Endeavour in British Columbia, Vancouver, Canada. maja@cmmt.ubc.ca.
authors.forename: Maja
authors.initials: M
authors.lastname: Tarailo-Graovac
authors.affiliation: Treatable Intellectual Disability Endeavour in British Columbia, Vancouver, Canada. gsinclair@cw.bc.ca.|Division of Biochemical Diseases, Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, Canada. gsinclair@cw.bc.ca.|Biochemical Genetics Laboratory, Department of Pathology, BC Children's Hospital, University of British Columbia, Vancouver, Canada. gsinclair@cw.bc.ca.
authors.forename: Graham
authors.initials: G
authors.lastname: Sinclair
authors.affiliation: Treatable Intellectual Disability Endeavour in British Columbia, Vancouver, Canada. sstockler@cw.bc.ca.|Division of Biochemical Diseases, Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, Canada. sstockler@cw.bc.ca.|Child & Family Research Institute, Vancouver, BC, Canada. sstockler@cw.bc.ca.
authors.forename: Sylvia
authors.initials: S
authors.lastname: Stockler-Ipsiroglu
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, Canada. mvallen@cw.bc.ca.|Child & Family Research Institute, Vancouver, BC, Canada. mvallen@cw.bc.ca.
authors.forename: Margot
authors.initials: M
authors.lastname: Van Allen
authors.affiliation: Division of Hematology, Oncology & BMT, Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, Canada. jrozmus@cw.bc.ca.|Child & Family Research Institute, Vancouver, BC, Canada. jrozmus@cw.bc.ca.
authors.forename: Jacob
authors.initials: J
authors.lastname: Rozmus
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Vancouver, Canada. casper@cmmt.ubc.ca.|Department of Medical Genetics, University of British Columbia, Vancouver, Canada. casper@cmmt.ubc.ca.|Treatable Intellectual Disability Endeavour in British Columbia, Vancouver, Canada. casper@cmmt.ubc.ca.
authors.forename: Casper
authors.initials: C
authors.lastname: Shyr
authors.affiliation: Department of Paediatric Neurology, Children's Hospital Oxford, John Radcliffe Hospital, Oxford, UK. roberta@biancheri.com.
authors.forename: Roberta
authors.initials: R
authors.lastname: Biancheri
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, Canada. toh@cw.bc.ca.|Child & Family Research Institute, Vancouver, BC, Canada. toh@cw.bc.ca.
authors.forename: Tracey
authors.initials: T
authors.lastname: Oh
authors.affiliation: Treatable Intellectual Disability Endeavour in British Columbia, Vancouver, Canada. Bryan.Sayson@cw.bc.ca.|Division of Biochemical Diseases, Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, Canada. Bryan.Sayson@cw.bc.ca.
authors.forename: Bryan
authors.initials: B
authors.lastname: Sayson
authors.affiliation: Treatable Intellectual Disability Endeavour in British Columbia, Vancouver, Canada. MLafek@cw.bc.ca.|Division of Biochemical Diseases, Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, Canada. MLafek@cw.bc.ca.
authors.forename: Mirafe
authors.initials: M
authors.lastname: Lafek
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Vancouver, Canada. colinross1@gmail.com.|Department of Medical Genetics, University of British Columbia, Vancouver, Canada. colinross1@gmail.com.|Treatable Intellectual Disability Endeavour in British Columbia, Vancouver, Canada. colinross1@gmail.com.|Child & Family Research Institute, Vancouver, BC, Canada. colinross1@gmail.com.
authors.forename: Colin J
authors.initials: CJ
authors.lastname: Ross
authors.affiliation: Department of Medical Genetics, University of British Columbia, Vancouver, Canada. wrobinson@cfri.ca.|Child & Family Research Institute, Vancouver, BC, Canada. wrobinson@cfri.ca.
authors.forename: Wendy P
authors.initials: WP
authors.lastname: Robinson
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Vancouver, Canada. wyeth@cmmt.ubc.ca.|Department of Medical Genetics, University of British Columbia, Vancouver, Canada. wyeth@cmmt.ubc.ca.|Treatable Intellectual Disability Endeavour in British Columbia, Vancouver, Canada. wyeth@cmmt.ubc.ca.|Child & Family Research Institute, Vancouver, BC, Canada. wyeth@cmmt.ubc.ca.
authors.forename: Wyeth W
authors.initials: WW
authors.lastname: Wasserman
authors.affiliation: Department of Neuroradiology, Istituto Giannina Gaslini, Via Gerolamo Gaslini 5, I-16147, Genoa, Italy. andrearossi@ospedale-gaslini.ge.it.
authors.forename: Andrea
authors.initials: A
authors.lastname: Rossi
authors.affiliation: Centre for Molecular Medicine and Therapeutics, Vancouver, Canada. cvankarnebeek@cw.bc.ca.|Treatable Intellectual Disability Endeavour in British Columbia, Vancouver, Canada. cvankarnebeek@cw.bc.ca.|Division of Biochemical Diseases, Department of Pediatrics, BC Children's Hospital, University of British Columbia, Vancouver, Canada. cvankarnebeek@cw.bc.ca.|Child & Family Research Institute, Vancouver, BC, Canada. cvankarnebeek@cw.bc.ca.
authors.forename: Clara D M
authors.initials: CD
authors.lastname: van Karnebeek
mesh_terms: D000595:Amino Acid Sequence; D005838:Genotype; D018095:Germ-Line Mutation; D006801:Humans; D007223:Infant; D008297:Male; D008565:Membrane Proteins / Q000172:deficiency / Q000235:genetics* / Q000378:metabolism*; D008969:Molecular Sequence Data; D020125:Mutation, Missense
chemical_list: D008565:Membrane Proteins; C080086:phosphatidylinositol glycan-class A protein