title: PGAP3-related hyperphosphatasia with mental retardation syndrome: Report of 10 new patients and a homozygous founder mutation.
abstract: BACKGROUND
  Hyperphosphatasia with mental retardation syndrome (HPMRS) is caused by recessive mutations in genes involved in the glycosylphosphatidylinsitol pathway, including PGAP3.
  
  
  METHODS
  We describe 10 patients from 8 Egyptian families presenting with developmental delay, severe intellectual disability, distinct facial dysmorphism and increased alkaline phosphatase. Sanger sequencing of PGAP3 was performed.
  
  
  RESULTS
  Eight patients had cleft palate, 4 had postnatal microcephaly and 5 had seizures. Neuro-imaging findings showed thin corpus callosum in 9 patients, mild ventriculomegaly in 3 patients and variable degrees of cerebellar vermis hypoplasia in 4 patients, a finding not previously reported in patients with HPMRS. Additional manifestations included double row teeth, hypogenitalism and congenital heart disease. Biallelic loss of function mutations in the PGAP3 gene were detected in all patients. Nine patients were homozygous for the c.402dupC (p.M135Hfs*28) mutation strongly suggesting a founder effect. On the other hand, 1 patient had a novel mutation, c.817_820delGACT (p.D273Sfs*37).
  
  
  CONCLUSIONS
  This is the largest series of patients with HPMRS from same ethnic group. Our results reinforce the distinct clinical and facial features of PGAP3-related HPMRS which are the clue for targeted genetic testing. Moreover, we present additional unreported clinical and neuro-imaging findings and a novel mutation thus expanding the phenotypic and mutational spectrum of this rare disorder.
authors.affiliation: Medical Molecular Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
authors.forename: M S
authors.initials: MS
authors.lastname: Abdel-Hamid
authors.affiliation: Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
authors.forename: M Y
authors.initials: MY
authors.lastname: Issa
authors.affiliation: Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
authors.forename: G A
authors.initials: GA
authors.lastname: Otaify
authors.affiliation: Medical Molecular Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
authors.forename: S F
authors.initials: SF
authors.lastname: Abdel-Ghafar
authors.affiliation: Child Health Department, Medical Research Division, National Research Centre, Cairo, Egypt.
authors.forename: H M
authors.initials: HM
authors.lastname: Elbendary
authors.affiliation: Clinical Genetics Department, Human Genetics and Genome Research Division, National Research Centre, Cairo, Egypt.
authors.forename: M S
authors.identifier: http://orcid.org/0000-0001-7840-0002
authors.initials: MS
authors.lastname: Zaki
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000473:pathology; D001483:Base Sequence; D002265:Carboxylic Ester Hydrolases; D003241:Consanguinity; D004534:Egypt; D005192:Family Health; D005260:Female; D018703:Founder Effect; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008607:Intellectual Disability / Q000235:genetics* / Q000473:pathology; D008297:Male; D009154:Mutation; D010375:Pedigree; D010641:Phenotype; D010760:Phosphorus Metabolism Disorders / Q000235:genetics* / Q000473:pathology; D011956:Receptors, Cell Surface / Q000235:genetics*; D017422:Sequence Analysis, DNA / Q000379:methods
chemical_list: D011956:Receptors, Cell Surface; D002265:Carboxylic Ester Hydrolases; C476212:PGAP3 protein, human
keywords: Mabry syndrome; PGAP3 gene; founder mutation; glycosylphosphatidylinositol; hyperphosphatasia; mental retardation