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

Am J Hum Genet. 2018 Oct 04;103(4):602-611. Epub 2018 Sep 27

Thi Tuyet Mai Nguyen ¹ , Yoshiko Murakami ² , Kristen M Wigby ³ , Nissan V Baratang ¹ , Justine Rousseau ¹ ,

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

+ et al

Author information

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: p.campeau@umontreal.ca.

摘要

Inherited GPI deficiencies (IGDs) are a subset of congenital disorders of glycosylation that are increasingly recognized as a result ofÂ 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^â) 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^â 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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