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

Saskia N van der Crabben, Magdalena Harakalova, Eva H Brilstra, Frédérique M C van Berkestijn, Floris C Hofstede, Adrianus J van Vught, Edwin Cuppen, Wigard Kloosterman, Hans Kristian Ploos van Amstel, Gijs van Haaften, Mieke M van Haelst

Research output: Contribution to journalReview articleAcademicpeer-review

35 Citations (Scopus)


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.

Original languageEnglish
Pages (from-to)29-35
Number of pages7
JournalAmerican Journal of Medical Genetics Part A
Issue number1
Publication statusPublished - Jan 2014


  • Abnormalities, Multiple/diagnosis
  • Alkaline Phosphatase/blood
  • Brain/pathology
  • Chromosome Segregation
  • Chromosomes, Human, X
  • Developmental Disabilities/diagnosis
  • Exome
  • Germ-Line Mutation
  • High-Throughput Nucleotide Sequencing
  • Humans
  • Infant
  • Magnetic Resonance Imaging
  • Male
  • Membrane Proteins/genetics
  • Pedigree
  • Phenotype
  • X Chromosome Inactivation

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