Cerebral visual impairment and intellectual disability caused by PGAP1 variants

Eur J Hum Genet. 2015 Dec;23(12):1689-93. doi: 10.1038/ejhg.2015.42. Epub 2015 Mar 25.


Homozygous variants in PGAP1 (post-GPI attachment to proteins 1) have recently been identified in two families with developmental delay, seizures and/or spasticity. PGAP1 is a member of the glycosylphosphatidylinositol anchor biosynthesis and remodeling pathway and defects in this pathway are a subclass of congenital disorders of glycosylation. Here we performed whole-exome sequencing in an individual with cerebral visual impairment (CVI), intellectual disability (ID), and factor XII deficiency and revealed compound heterozygous variants in PGAP1, c.274_276del (p.(Pro92del)) and c.921_925del (p.(Lys308Asnfs*25)). Subsequently, PGAP1-deficient Chinese hamster ovary (CHO)-cell lines were transfected with either mutant or wild-type constructs and their sensitivity to phosphatidylinositol-specific phospholipase C (PI-PLC) treatment was measured. The mutant constructs could not rescue the PGAP1-deficient CHO cell lines resistance to PI-PLC treatment. In addition, lymphoblastoid cell lines (LCLs) of the affected individual showed no sensitivity to PI-PLC treatment, whereas the LCLs of the heterozygous carrier parents were partially resistant. In conclusion, we report novel PGAP1 variants in a boy with CVI and ID and a proven functional loss of PGAP1 and show, to our knowledge, for the first time this genetic association with CVI.

Publication types

  • Case Reports
  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • Cell Line, Tumor
  • Child
  • Cricetinae
  • Cricetulus
  • Humans
  • Intellectual Disability / diagnosis
  • Intellectual Disability / genetics*
  • Male
  • Membrane Proteins / genetics*
  • Membrane Proteins / metabolism
  • Mutation*
  • Phosphoinositide Phospholipase C / metabolism
  • Phosphoric Monoester Hydrolases / genetics*
  • Phosphoric Monoester Hydrolases / metabolism
  • Syndrome
  • Vision Disorders / diagnosis
  • Vision Disorders / genetics*
  • Visual Perception


  • Membrane Proteins
  • PGAP1 protein, human
  • Phosphoric Monoester Hydrolases
  • Phosphoinositide Phospholipase C