title: Compound heterozygous variants in PGAP1 causing severe psychomotor retardation, brain atrophy, recurrent apneas and delayed myelination: a case report and literature review.
abstract: BACKGROUND
  Mutations in proteins involved in the glycosylphosphatidylinositol anchor biosynthesis and remodeling pathway are associated with autosomal recessive forms of intellectual disability. Recently mutations in the PGAP1 gene that codes for PGAP1, a protein localized in the endoplasmic reticulum responsible for the first step of the remodeling of glycosylphosphatidylinositol was linked to a disorder characterized by psychomotor retardation and facial dysmorphism. Whole exome sequencing (WES) was performed in siblings with severely delayed myelination and psychomotor retardation. Mutations in PGAP1 were confirmed by Sanger sequencing and RNA analysis. A literature search was performed to describe the emerging phenotype of PGAP1 related disease.
  
  
  METHODS
  WES resulted in the detection of two novel compound heterozygous mutations in PGAP1, one base pair insertion leading to a frame shift c.334_335InsA (p.A112fs) and a splice site mutation leading to exon skipping c.G1173C (p.L391L). A symptom not described in PGAP1 related disorder before but prominent in the siblings were recurrent apnea especially during sleep that persisted at least until age 2 years. Sequential cerebral MRI at age one and two year(s) respectively revealed frontal accentuated brain atrophy and significantly delayed myelination.
  
  
  CONCLUSIONS
  We report siblings with two novel mutations in PGAP1. Other that the common symptoms related to PGAP1 mutations including non-progressive psychomotor retardation, neonatal feeding problems, microcephaly and brain atrophy these patients displayed severely delayed myelination and recurrent apneas thereby widing the clinical spectrum associated with such mutations.
authors.affiliation: Department of Pediatrics and Pediatric Neurology, University Medical Center, Georg August University, 37075, Göttingen, Germany. matthias.kettwig@med.uni-goettingen.de.
authors.forename: Matthias
authors.initials: M
authors.lastname: Kettwig
authors.affiliation: Monique and Jacques Roboh Department of Genetic Research, Hadassah-Hebrew University Medical Center, Jerusalem, Israel.
authors.forename: Orly
authors.initials: O
authors.lastname: Elpeleg
authors.affiliation: Department of Pediatrics and Pediatric Neurology, University Medical Center, Georg August University, 37075, Göttingen, Germany.
authors.forename: Eike
authors.initials: E
authors.lastname: Wegener
authors.affiliation: Department of Pediatrics and Pediatric Neurology, University Medical Center, Georg August University, 37075, Göttingen, Germany.
authors.forename: Steffi
authors.initials: S
authors.lastname: Dreha-Kulaczewski
authors.affiliation: Department of Pediatrics and Pediatric Neurology, University Medical Center, Georg August University, 37075, Göttingen, Germany.
authors.forename: Marco
authors.initials: M
authors.lastname: Henneke
authors.affiliation: Department of Pediatrics and Pediatric Neurology, University Medical Center, Georg August University, 37075, Göttingen, Germany.
authors.forename: Jutta
authors.initials: J
authors.lastname: Gärtner
authors.affiliation: Department of Pediatrics and Pediatric Neurology, University Medical Center, Georg August University, 37075, Göttingen, Germany.
authors.forename: Peter
authors.initials: P
authors.lastname: Huppke
mesh_terms: D001049:Apnea / Q000235:genetics*; D001284:Atrophy / Q000000981:diagnostic imaging / Q000473:pathology*; D001921:Brain / Q000000981:diagnostic imaging / Q000473:pathology*; D001927:Brain Diseases / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D002675:Child, Preschool; D002658:Developmental Disabilities / Q000235:genetics* / Q000503:physiopathology; D006801:Humans; D008279:Magnetic Resonance Imaging; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D009154:Mutation; D009186:Myelin Sheath / Q000473:pathology*; D059906:Neuroimaging; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics*; D014429:Twins, Dizygotic / Q000235:genetics / Q000523:psychology
chemical_list: D008565:Membrane Proteins; C484857:PGAP1 protein, human; D010744:Phosphoric Monoester Hydrolases
keywords: Case report; Developmental Disabilities; Leukoencephalopathies; Neonatal seizures; PGAP1 mutations; Whole exome sequencing