PIGH deficiency can be associated with severe neurodevelopmental and skeletal manifestations.

Camille Tremblay‐Laganière,Jill A Madden,Wendy K Chung,Rauan Kaiyrzhanov,Philippe M Campeau,Reza Maroofian,Chanika Phornphutkul,Kamran Salayev,Thi Tuyet Mai Nguyen,Pankaj B Agrawal,Ilana T Chilton,Henry Houlden

doi:10.1111/cge.13877

Abstract

Phosphatidylinositol Glycan Anchor Biosynthesis class H (PIGH) is an essential player in the glycosylphosphatidylinositol (GPI) synthesis, an anchor for numerous cell membrane‐bound proteins. PIGH deficiency is a newly described and rare disorder associated with developmental delay, seizures and behavioral difficulties. Herein, we report three new unrelated families with two different bi‐allelic PIGH variants, including one new variant p.(Arg163Trp) which seems associated with a more severe phenotype. The common clinical features in all affected individuals are developmental delay/intellectual disability and hypotonia. Variable clinical features include seizures, autism spectrum disorder, apraxia, severe language delay, dysarthria, feeding difficulties, facial dysmorphisms, microcephaly, strabismus, and musculoskeletal anomalies. The two siblings homozygous for the p.(Arg163Trp) variant have severe symptoms including profound psychomotor retardation, intractable seizures, multiple bone fractures, scoliosis, loss of independent ambulation, and delayed myelination on brain MRI. Serum iron levels were significantly elevated in one individual. All tested individuals with PIGH deficiency had normal alkaline phosphatase and CD16, a GPI‐anchored protein (GPI‐AP), was found to be decreased by 60% on granulocytes from one individual. This study expands the PIGH deficiency phenotype range toward the severe end of the spectrum with the identification of a novel pathogenic variant.

Highlights

It is estimated that about 1% of the human proteome is anchored to the cell membrane by a glycosylphosphatidylinositol (GPI) anchor[1]
The core phenotype in this case series is delay/intellectual disability (DD/ID) combined with hypotonia
No speech or babbling were noted at 18 months old, and he is currently non-verbal

Summary

Introduction

It is estimated that about 1% of the human proteome is anchored to the cell membrane by a glycosylphosphatidylinositol (GPI) anchor[1]. Because of GPI-Aps’ importance in embryogenesis and neurogenesis, disruption of GPI biosynthesis results most commonly in developmental delay/intellectual disability (DD/ID), seizures, dysmorphisms and other nervous system abnormalities such as hypotonia, a group of diseases called inherited GPI deficiency disorders (IGDs)[2]. Phosphatidylinositol Glycan Anchor Biosynthesis class H (PIGH, MIM reference number 618010) is an essential component for GPI-GnT enzymatic activity in yeast[4]. There are only three reported cases from two families of individuals with bi-allelic PIGH variants in the literature[5,6]. Those individuals had DD/ID, seizures, behavioral difficulties, autism spectrum disorder, delayed language, microcephaly, mild dysmorphic features, normal alkaline phosphatase and non-specific brain MRI findings. We report three new unrelated families with two different bi-allelic PIGH variants, including one that was never reported before: p.(Arg163Trp)

Methods

Results

Conclusion