2. Academic Validation
  3. Mutations in PIGS, Encoding a GPI Transamidase, Cause a Neurological Syndrome Ranging from Fetal Akinesia to Epileptic Encephalopathy

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

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.

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