title: Expanding the spectrum of phenotypes associated with germline PIGA mutations: a child with developmental delay, accelerated linear growth, facial dysmorphisms, elevated alkaline phosphatase, and progressive CNS abnormalities.
abstract: Phosphatidyl inositol glycan (PIG) enzyme subclasses are involved in distinct steps of glycosyl phosphatidyl inositol anchor protein biosynthesis. Glycolsyl phosphatidyl inositol-anchored proteins have heterogeneous functions; they can function as enzymes, adhesion molecules, complement regulators and co-receptors in signal transduction pathways. Germline mutations in genes encoding different members of the PIG family result in diverse conditions with (severe) developmental delay, (neonatal) seizures, hypotonia, CNS abnormalities, growth abnormalities, and congenital abnormalities as hallmark features. The variability of clinical features resembles the typical diversity of other glycosylation pathway deficiencies such as the congenital disorders of glycosylation. Here, we report the first germline missense mutation in the PIGA gene associated with accelerated linear growth, obesity, central hypotonia, severe refractory epilepsy, cardiac anomalies, mild facial dysmorphic features, mildly elevated alkaline phosphatase levels, and CNS anomalies consisting of progressive cerebral atrophy, insufficient myelinization, and cortical MRI signal abnormalities. X-exome sequencing in the proband identified a c.278C>T (p.Pro93Leu) mutation in the PIGA gene. The mother and maternal grandmother were unaffected carriers and the mother showed 100% skewing of the X-chromosome harboring the mutation. These results together with the clinical similarity of the patient reported here and the previously reported patients with a germline nonsense mutation in PIGA support the determination that this mutation caused the phenotype in this family.
authors.affiliation: Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands.
authors.forename: Saskia N
authors.initials: SN
authors.lastname: van der Crabben
authors.forename: Magdalena
authors.initials: M
authors.lastname: Harakalova
authors.forename: Eva H
authors.initials: EH
authors.lastname: Brilstra
authors.forename: Frédérique M C
authors.initials: FM
authors.lastname: van Berkestijn
authors.forename: Floris C
authors.initials: FC
authors.lastname: Hofstede
authors.forename: Adrianus J
authors.initials: AJ
authors.lastname: van Vught
authors.forename: Edwin
authors.initials: E
authors.lastname: Cuppen
authors.forename: Wigard
authors.initials: W
authors.lastname: Kloosterman
authors.forename: Hans Kristian
authors.initials: HK
authors.lastname: Ploos van Amstel
authors.forename: Gijs
authors.initials: G
authors.lastname: van Haaften
authors.forename: Mieke M
authors.initials: MM
authors.lastname: van Haelst
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics*; D000469:Alkaline Phosphatase / Q000097:blood*; D001921:Brain / Q000473:pathology; D020090:Chromosome Segregation; D041321:Chromosomes, Human, X; D002658:Developmental Disabilities / Q000175:diagnosis / Q000235:genetics*; D059472:Exome; D018095:Germ-Line Mutation; D059014:High-Throughput Nucleotide Sequencing; D006801:Humans; D007223:Infant; D008279:Magnetic Resonance Imaging; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D010375:Pedigree; D010641:Phenotype; D049951:X Chromosome Inactivation
chemical_list: D008565:Membrane Proteins; C080086:phosphatidylinositol glycan-class A protein; D000469:Alkaline Phosphatase
keywords: GPI biosynthesis pathway; PIGA gene; accelerated linear growth; alkaline phosphatase; congenital disorder of glycosylation; progressive brain anomalies; refractory epilepsy