A homozygous variant disrupting the PIGH start-codon is associated with developmental delay, epilepsy, and microcephaly

Hum Mutat. 2018 Jun;39(6):822-826. doi: 10.1002/humu.23420. Epub 2018 Mar 30.


Defective glycosylphosphatidylinositol (GPI)-anchor biogenesis can cause a spectrum of predominantly neurological problems. For eight genes critical to this biological process, disease associations are not yet reported. Scanning exomes from 7,833 parent-child trios and 1,792 singletons from the DDD study for biallelic variants in this gene-set uncovered a rare PIGH variant in a boy with epilepsy, microcephaly, and behavioral difficulties. Although only 2/2 reads harbored this c.1A > T transversion, the presence of ∼25 Mb autozygosity at this locus implied homozygosity, which was confirmed using Sanger sequencing. A similarly-affected sister was also homozygous. FACS analysis of PIGH-deficient CHO cells indicated that cDNAs with c.1A > T could not efficiently restore expression of GPI-APs. Truncation of PIGH protein was consistent with the utilization of an in-frame start-site at codon 63. In summary, we describe siblings harboring a homozygous c.1A > T variant resulting in defective GPI-anchor biogenesis and highlight the importance of exploring low-coverage variants within autozygous regions.

Keywords: GPI-anchor biogenesis; PIGH; developmental delay; exome; microcephaly; phosphatidylinositol N-acetylglucosaminyltransferase.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Animals
  • Child
  • Child, Preschool
  • Codon, Initiator / genetics
  • Cricetinae
  • Developmental Disabilities / genetics*
  • Developmental Disabilities / physiopathology
  • Epilepsy / genetics*
  • Epilepsy / physiopathology
  • Exome / genetics
  • Female
  • Glycosylphosphatidylinositols / genetics
  • Humans
  • Male
  • Membrane Proteins / genetics*
  • Microcephaly / genetics*
  • Microcephaly / physiopathology
  • Mutation
  • Pedigree


  • Codon, Initiator
  • Glycosylphosphatidylinositols
  • Membrane Proteins
  • PIGH protein, human