Mutations in PIGS, Encoding a GPI Transamidase, Cause a Neurological Syndrome Ranging from Fetal Akinesia to Epileptic Encephalopathy

  • Am J Hum Genet. 2018 Oct 4;103(4):602-611. doi: 10.1016/j.ajhg.2018.08.014.
Thi Tuyet Mai Nguyen  1 ,  Yoshiko Murakami  2 ,  Kristen M Wigby  3 ,  Nissan V Baratang  1 ,  Justine Rousseau  1 ,  Anik St-Denis  1 ,  Jill A Rosenfeld  4 ,  Stephanie C Laniewski  5 ,  Julie Jones  6 ,  Alejandro D Iglesias  7 ,  Marilyn C Jones  3 ,  Diane Masser-Frye  8 ,  Angela E Scheuerle  9 ,  Denise L Perry  10 ,  Ryan J Taft  10 ,  Françoise Le Deist  1 ,  Miles Thompson  3 ,  Taroh Kinoshita  2 ,  Philippe M Campeau  11
Affiliations
  • 1. Centre Hospitalier Universitaire Sainte Justine Research Center, University of Montreal, Montreal, QC H3T1C5, Canada.
  • 2. Research Institute for Microbial Diseases, Osaka University, Osaka 565-0871, Japan.
  • 3. Department of Pediatrics, University of California, San Diego, San Diego, CA 92093, USA.
  • 4. Department of Molecular & Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
  • 5. University of Rochester Medical Center, New York, NY 14642, USA.
  • 6. Greenwood Genetic Center, Greenwood, SC 29646, USA.
  • 7. NewYork-Presbyterian Morgan Stanley Children's Hospital, New York, NY 10032, USA.
  • 8. Rady Children's Hospital-San Diego, San Diego, CA 92123, USA.
  • 9. University of Texas, Southwestern Medical Center, Dallas, TX, USA.
  • 10. Illumina Inc., San Diego, CA 92121, USA.
  • 11. Centre Hospitalier Universitaire Sainte Justine Research Center, University of Montreal, Montreal, QC H3T1C5, Canada. Electronic address: [email protected].
PMID: 30269814 DOI: 10.1016/j.ajhg.2018.08.014
Abstract

Inherited GPI deficiencies (IGDs) are a subset of congenital disorders of glycosylation that are increasingly recognized as a result of advances in whole-exome Sequencing (WES) and whole-genome Sequencing (WGS). IGDs cause a series of overlapping phenotypes consisting of seizures, dysmorphic features, multiple congenital malformations, and severe intellectual disability. We present a study of six individuals from three unrelated families in which WES or WGS identified bi-allelic phosphatidylinositol glycan class S (PIGS) biosynthesis mutations. Phenotypes included severe global developmental delay, seizures (partly responding to pyridoxine), hypotonia, weakness, ataxia, and dysmorphic facial features. Two of them had compound-heterozygous variants c.108G>A (p.Trp36∗) and c.101T>C (p.Leu34Pro), and two siblings of another family were homozygous for a deletion and insertion leading to p.Thr439_Lys451delinsArgLeuLeu. The third family had two fetuses with multiple joint contractures consistent with fetal akinesia. They were compound heterozygous for c.923A>G (p.Glu308Gly) and c.468+1G>C, a splicing mutation. Flow-cytometry analyses demonstrated that the individuals with PIGS mutations show a GPI-AP deficiency profile. Expression of the p.Trp36∗ variant in PIGS-deficient HEK293 cells revealed only partial restoration of cell-surface GPI-APs. In terms of both biochemistry and phenotype, loss of function of PIGS shares features with PIGT deficiency and Other IGDs. This study contributes to the understanding of the GPI-AP biosynthesis pathway by describing the consequences of PIGS disruption in humans and extending the family of IGDs.

Keywords
PIGS; epilepsy; glycosylphosphatidylinositol; glycosylphosphatidylinositol biosynthesis defect; inherited GPI deficiency; seizures.