GPAA1 – Glycosylphosphatidylinositol Biosynthesis Defect 15

Glycosylphosphatidylinositol (GPI) Biosynthesis Defect 15 is a rare autosomal recessive disorder caused by biallelic loss of function of GPAA1 and is catalogued as Glycosylphosphatidylinositol biosynthesis defect 15. Patients typically present in early childhood with global developmental delay, hypotonia, intellectual disability, seizures, and cerebellar atrophy. To date, fewer than twenty affected individuals have been reported, most compound heterozygous; recent publications describe novel homozygous and compound heterozygous variants supporting an autosomal recessive inheritance model.

A single-patient report detailed a 4-year-old male with a novel homozygous variant c.424G>A (p.Glu142Lys) presenting with intellectual disability, hypotonia, seizures, global developmental delay, macrocephaly, and cerebellar atrophy initially absent at 15 months but evident by 33 months ([PMID:37510348]). This case confirms the core phenotype of GPI anchoring deficiency in GPAA1 and expands the clinical spectrum with macrocephaly and preauricular appendages.

An international case series of seven additional probands identified ten novel biallelic GPAA1 variants, including six missense and four predicted loss-of-function alleles, all in trans, in individuals with developmental delay, seizures, hypotonia, and cerebellar anomalies ([PMID:34703884]). Flow cytometry in three patients confirmed deficiency of multiple GPI-anchored proteins on leukocytes, consistent with pathogenic impairment of GPI transamidase activity.

Across the eight unrelated probands, the variant spectrum comprises missense substitutions (e.g., c.424G>A (p.Glu142Lys), c.947C>T (p.Ala316Val)) and frameshift alleles (e.g., c.1477_1478del (p.Arg493fs)), with no recurrent or founder variants reported. Alkaline phosphatase levels are variably normal or reduced, paralleling other subunits of the transamidase complex.

Functional studies demonstrate that patient-derived leukocytes exhibit marked reduction of GPI-anchored proteins by flow cytometry ([PMID:34703884]), establishing a mechanistic link between GPAA1 deficiency and impaired GPI anchoring. Animal or cellular rescue models in human GPAA1 deficiency remain to be reported.

Collectively, eight probands from eight families with biallelic GPAA1 variants and concordant functional data support a Moderate clinical validity for GPAA1 in GPI Biosynthesis Defect 15. Genetic testing for GPAA1 variants is clinically useful for diagnosis and prognosis. Key take-home: Biallelic GPAA1 variants cause a consistent GPI-anchoring deficiency phenotype, and flow cytometry of GPI-anchored proteins is a valuable diagnostic adjunct.

References

• Genes • 2023 • A Novel Homozygous GPAA1 Variant in a Patient with a Glycosylphosphatidylinositol Biosynthesis Defect. PMID:37510348
• Neurology. Genetics • 2021 • Expanding the Phenotypic Spectrum of GPI Anchoring Deficiency Due to Biallelic Variants in GPAA1. PMID:34703884

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