Glycosylphosphatidylinositol biosynthesis defects cause rare genetic disorders characterised by developmental delay/ intellectual disability, seizures, dysmorphic features, and diverse congenital anomalies associated with a wide range of additional features (hypotonia, hearing loss, elevated alkaline phosphatase, and several other features). Glycosylphosphatidylinositol functions as an anchor to link cell membranes and protein. These proteins function as enzymes, adhesion molecules, complement regulators, or co-receptors in signal transduction pathways. Biallelic variants involved in the glycosylphosphatidylinositol anchored proteins biosynthetic pathway are responsible for a growing number of disorders, including multiple congenital anomalies-hypotonia-seizures syndrome; hyperphosphatasia with mental retardation syndrome/Mabry syndrome; coloboma, congenital heart disease, ichthyosiform dermatosis, mental retardation, and ear anomalies/epilepsy syndrome; and early infantile epileptic encephalopathy-55. This review focuses on the current understanding of Glycosylphosphatidylinositol biosynthesis defects and the associated genes to further understand its wide phenotype spectrum.

PIGT encodes a subunit of the glycosylphosphatidylinositol transamidase complex, which catalyzes the attachment of proteins to GPI-anchors. A homozygous PIGT variant c.550G>A (p. E184K) in a Chinese boy with multiple malformations, hypotonia, seizure and profound development delay was identified by panel sequencing. Pathogenicity of the variant was confirmed by flow cytometry. The expression of CD16 and CD24 of this proband reduced to 16.92 and 22.16% compare with normal control respectively while which of his parents and sister were normal. This mutation raised the mRNA level on the peripheral blood mono nuclear cells of this patient. This study expanded the variant spectrum of MCAHS3, and CD16 could be an effective marker to evaluate the pathogenicity of PIGT mutation.

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