Homozygous PGAP2 mutation cause hyperphosphatasia with mental retardation syndrome-3 (HPMRS3): Genetic and clinical evaluation of the ultra rare inherited glycosylphosphatidylinositol (GPI) biosynthesis defect
2Lokman Hekim Univercity, Turkiye
3İntergen Genetic Center, Turkiye
BACKGROUND
Inherited glycosylphosphatidylinositol biosynthesis defect is considered a subset of the congenital glycosylation disorder that result from mutations in the genes encoding proteins participating in glycosylphosphatidylinositol biosynthesis and modification. 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.
METHODS
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, corpus callosum hypoplasia.Whole exome sequencing revealed a homozygous c.651C>G (p.His217Gln) in the PGAP2 gene. The Sanger sequencing confirmed the parents were heterozygous. Next generation sequencing, whole transcriptome sequencing and homology modelling and analysis were performed. There is no splicing variant was detected by whole transcriptome sequencing. The AlphaFold model was interpreted hypothetically. It was observed the substitution of histidine, with glutamine and may affect the stability of protein.
RESULTS
WES was performed on the patient for diagnosis, and while no significant copy number variation was identified from the WES data, a homozygous novel mutation c.651C>G (p.His217Gln) in the PGAP2 gene was revealed.
DISCUSSION/CONCLUSION
Homozygous PGAP2 mutations in the patient we reported in our study resulted in a severe clinic including, severe intellectual disability, severe epilepsia, dysmorphic features, central fever, biochemical, hormonal and immunological abnormalities.We showed that, the instability of mutant PGAP2 protein that cause Hyperphosphatasia with mental retardation syndrome-3 lead to more severe phenotypes.
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