Homozygous PGAP2 Mutation Causes Hyperphosphatasia with Mental Retardation Syndrome-3: Genetic and Clinical Evaluation of the Ultra-Rare Inherited Glycosylphosphatidylinositol Biosynthesis Defect.

Introduction: Inherited glycosylphosphatidylinositol biosynthesis defect is considered a subset of the congenital glycosylation disorder that results from mutations in the genes encoding proteins participating in glycosylphosphatidylinositol biosynthesis and modification. Glycosylphosphatidylinositol anchor proteins play important roles in numerous cellular processes including neurogenesis, cell adhesion, immune response, and signaling. Hyperphosphatasia with mental retardation syndrome-3 is one of the glycosylphosphatidylinositol anchor defects, characterized by moderate to severe intellectual disability, dysmorphic features, hypotonia, seizures, and persistent hyperphosphatasia. The aims of this study were to investigate the clinical implications of the PGAP2 gene and identify the severe phenotype.

Case presentation: A male patient with dysmorphic features, neurodevelopmental delay, seizures, hearing loss, Hirschsprung disease, central fever, and elevated alkaline phosphatase was included in the study. The magnetic resonance imaging showed cerebral atrophy and corpus callosum hypoplasia. The whole-exome sequencing analysis of the individual and Sanger sequencing were performed for segregation. Additionally, next-generation sequencing, whole transcriptome sequencing, and homology modeling and analysis were performed. Whole-exome sequencing revealed a homozygous c.651C>G (p.His217Gln) in the PGAP2 gene. The Sanger sequencing confirmed the parents were heterozygous. There is no splicing variant detected by whole transcriptome sequencing. The AlphaFold model was interpreted hypothetically. It observed the substitution of histidine, with glutamine, and may affect the stability of protein.

Discussion: Homozygous PGAP2 mutations in the patient we reported in our study resulted in a severe clinical picture including severe developmental delay and intellectual disability, severe epilepsy, dysmorphic features, central fever, biochemical, hormonal, and immunological abnormalities. This patient would be the youngest case published in the literature. We showed that the instability of mutant PGAP2 protein that causes hyperphosphatasia with mental retardation syndrome-3 leads to more severe phenotypes.