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

• Published in: American journal of human genetics Vol. 103; no. 4; pp. 602 - 611
• Main Authors: Nguyen, Thi Tuyet Mai, Murakami, Yoshiko, Wigby, Kristen M., Baratang, Nissan V., Rousseau, Justine, St-Denis, Anik, Rosenfeld, Jill A., Laniewski, Stephanie C., Jones, Julie, Iglesias, Alejandro D., Jones, Marilyn C., Masser-Frye, Diane, Scheuerle, Angela E., Perry, Denise L., Taft, Ryan J., Le Deist, Françoise, Thompson, Miles, Kinoshita, Taroh, Campeau, Philippe M.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 04.10.2018; Elsevier
• Subjects: epilepsy; glycosylphosphatidylinositol; glycosylphosphatidylinositol biosynthesis defect; inherited GPI deficiency; PIGS; seizures; PIGS; epilepsy; glycosylphosphatidylinositol biosynthesis defect; seizures; glycosylphosphatidylinositol; inherited GPI deficiency
• ISSN: 0002-9297; 1537-6605
• DOI: 10.1016/j.ajhg.2018.08.014

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.