TY - JOUR
T1 - Mutations in PIGS, Encoding a GPI Transamidase, Cause a Neurological Syndrome Ranging from Fetal Akinesia to Epileptic Encephalopathy
AU - Nguyen, Thi Tuyet Mai
AU - Murakami, Yoshiko
AU - Wigby, Kristen M.
AU - Baratang, Nissan V.
AU - Rousseau, Justine
AU - St-Denis, Anik
AU - Rosenfeld, Jill A.
AU - Laniewski, Stephanie C.
AU - Jones, Julie
AU - Iglesias, Alejandro D.
AU - Jones, Marilyn C.
AU - Masser-Frye, Diane
AU - Scheuerle, Angela E.
AU - Perry, Denise L.
AU - Taft, Ryan J.
AU - Le Deist, Françoise
AU - Thompson, Miles
AU - Kinoshita, Taroh
AU - Campeau, Philippe M.
N1 - Funding Information:
We acknowledge funding by the Canadian Institutes of Health Research (grant RN 324373 ), the Fonds de Recherche en Santé Québec (award 30647 ), and the Fondation du Grand Défi Pierre Lavoie . Whole-genome sequencing of family 2 was supported by the Illumina iHope program.
PY - 2018/10/4
Y1 - 2018/10/4
N2 - 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.
AB - 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.
KW - PIGS
KW - epilepsy
KW - glycosylphosphatidylinositol
KW - glycosylphosphatidylinositol biosynthesis defect
KW - inherited GPI deficiency
KW - seizures
UR - http://www.scopus.com/inward/record.url?scp=85054423529&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85054423529&partnerID=8YFLogxK
U2 - 10.1016/j.ajhg.2018.08.014
DO - 10.1016/j.ajhg.2018.08.014
M3 - Article
C2 - 30269814
AN - SCOPUS:85054423529
VL - 103
SP - 602
EP - 611
JO - American Journal of Human Genetics
JF - American Journal of Human Genetics
SN - 0002-9297
IS - 4
ER -