Compound heterozygous variants in PGAP1 causing severe psychomotor retardation, brain atrophy, recurrent apneas and delayed myelination: a case report and literature review

Abstract

BackgroundMutations in proteins involved in the glycosylphosphatidylinositol anchor biosynthesis and remodeling pathway are associated with autosomal recessive forms of intellectual disability. Recently mutations in the PGAP1 gene that codes for PGAP1, a protein localized in the endoplasmic reticulum responsible for the first step of the remodeling of glycosylphosphatidylinositol was linked to a disorder characterized by psychomotor retardation and facial dysmorphism. Whole exome sequencing (WES) was performed in siblings with severely delayed myelination and psychomotor retardation. Mutations in PGAP1 were confirmed by Sanger sequencing and RNA analysis. A literature search was performed to describe the emerging phenotype of PGAP1 related disease.Case presentationWES resulted in the detection of two novel compound heterozygous mutations in PGAP1, one base pair insertion leading to a frame shift c.334_335InsA (p.A112fs) and a splice site mutation leading to exon skipping c.G1173C (p.L391L). A symptom not described in PGAP1 related disorder before but prominent in the siblings were recurrent apnea especially during sleep that persisted at least until age 2 years. Sequential cerebral MRI at age one and two year(s) respectively revealed frontal accentuated brain atrophy and significantly delayed myelination.ConclusionWe report siblings with two novel mutations in PGAP1. Other that the common symptoms related to PGAP1 mutations including non-progressive psychomotor retardation, neonatal feeding problems, microcephaly and brain atrophy these patients displayed severely delayed myelination and recurrent apneas thereby widing the clinical spectrum associated with such mutations.Electronic supplementary materialThe online version of this article (doi:10.1186/s12883-016-0602-7) contains supplementary material, which is available to authorized users.

Clinical variability in inherited glycosylphosphatidylinositol deficiency disorders

“…Only three patients had epilepsy, which was surprising considering almost all patients with mutations in other genes of the GPI biosynthesis pathway suffered from seizures, with the exception of patients with PGAP2 mutations where less than half of the patients were affected. Furthermore, only a minority of patients had facial dysmorphism which was also unexpected as dysmorphic features were known as a common phenotype in patients with GPI disorders …”

“…Furthermore, only a minority of patients had facial dysmorphism which was also unexpected as dysmorphic features were known as a common phenotype in patients with GPI disorders. 36,[39][40][41][42][43][44] The abnormal structure of the GPI-APs' membrane anchors does not seem to translate into life-threatening phenotypes or obvious malformations in patients with mutations in the PGAP1 gene. However, affected patients still suffer severe intellectual deficiency with other neurological anomalies.…”

N-Glycan–dependent protein folding and endoplasmic reticulum retention regulate GPI-anchor processing

“…This effect was probably attributable to perturbation of Cripto and/or Wnt signaling ( Ueda et al, 2007 ; Zoltewicz et al, 2009 ; McKean and Niswander, 2012 ). It was reported that PGAP1 defects in human patients caused intellectual disability and encephalopathy ( Murakami et al, 2014 ; Granzow et al, 2015 ; Kettwig et al, 2016 ). These results suggest that the fine structure of GPI is important during development.…”

A likely pathogenic variant putatively affecting splicing of PIGA identified in a multiple congenital anomalies hypotonia‐seizures syndrome 2 (MCAHS2) family pedigree via whole‐exome sequencing

“…In particular, a lethal homozygous splicing defective variant in PIGN was identified in a fetus of syndromic congenital diaphragmatic hernia, which did not survive to birth mostly due to severe dysfunction of the protein (Brady et al., ). Also, at least three splicing defective variants of PGAP1 (MIM 611655) have been reported in autosomal recessive mental retardation‐42 (MRT42, MIM 615802) and related syndromes with psychomotor retardation and brain atrophy as well as other features (Granzow et al., ; Kettwig et al., ; Novarino et al., ). More IGD cases with splicing defective variants include one variant of PGAP3 (MIM 611801) in hyperphosphatasia with mental retardation syndrome 4 (HPMRS4, MIM 615716) (Knaus et al., ), two variants of PIGL (MIM 605947) in Chime syndrome (MIM 280000) and related neurodevelopmental disorder (Ng et al., ; Pagnamenta et al., ), one variant of PIGO (MIM 614730) in HPMRS2 (MIM 614749) (Krawitz et al., ), and one variant of PIGG (MIM 616918) in autosomal recessive mental retardation‐53 (MRT53, MIM 616917) (Makrythanasis et al., ), etc .…”