PIGA – Multiple Congenital Anomalies-Hypotonia-Seizures Syndrome 2

PIGA encodes the catalytic subunit of the glycosylphosphatidylinositol (GPI)‐N‐acetylglucosaminyltransferase complex, which initiates GPI‐anchor biosynthesis critical for anchoring diverse proteins to the cell surface. Germline PIGA variants at Xp22.2 cause multiple congenital anomalies-hypotonia-seizures syndrome 2 (MCAHS2; [MONDO:0010466]), an X-linked recessive disorder characterized by early-onset epilepsy, profound hypotonia, intellectual disability, and multisystem dysmorphisms (PMID:24357517).

Inheritance is X-linked recessive, with at least five unrelated male probands across four families presenting with hemizygous PIGA variants and consistent phenotypes (PMID:24357517; PMID:32256299; PMID:38927738; PMID:29974678). Segregation analysis demonstrates cosegregation of an early frameshift allele (c.76dup (p.Tyr26LeufsTer4)) in a large pedigree, with two affected brothers and multiple carrier females showing skewed X-inactivation patterns (PMID:24357517).

The variant spectrum includes early frameshift, missense, and splice-site changes. The recurrent early frameshift c.76dup (p.Tyr26LeufsTer4) allele and novel missense c.154C>T (p.His52Tyr) impair GPI-anchor synthesis; a hemizygous c.130C>G (p.Pro44Ala) and a splice-acceptor c.849-5A>G predicted to cause p.(Arg283SerfsTer15) have also been reported with equivalent severe phenotypes (PMID:24357517; PMID:32256299; PMID:29974678; PMID:38927738).

Functional studies in patient cells and heterologous systems confirm a hypomorphic mechanism. Flow cytometry of granulocytes and lymphocytes reveals reduced expression of GPI-anchored proteins such as CD16, CD59, and CD55. Complementation assays in PIGA-null cell lines show that translation reinitiation at Met37 yields a shortened PIGA protein that partially rescues CD59 surface expression, consistent with residual enzyme activity (PMID:24357517; PMID:32256299).

No studies to date robustly refute the PIGA–MCAHS2 association; all reported variants yield concordant clinical and cellular phenotypes. Additional variants and broader cohorts may further refine genotype–phenotype correlations.

Together, genetic and functional evidence support a Moderate clinical validity classification: multiple segregating variants across families with consistent phenotypes and hypomorphic functional data. Assessment of GPI-anchored protein expression by flow cytometry provides a rapid diagnostic adjunct. Key take-home: Hemizygous PIGA hypomorphic variants cause MCAHS2 via impaired GPI‐anchor biosynthesis, and targeted GPI-AP assays are clinically actionable for diagnosis and carrier detection.

References

• Human Mutation • 2014 • Early frameshift mutation in PIGA identified in a large XLID family without neonatal lethality. PMID:24357517
• Molecular Syndromology • 2020 • A Novel Mutation in PIGA Associated with Multiple Congenital Anomalies-Hypotonia-Seizure Syndrome 2 in a Boy with a Combination of Severe Epilepsy and Gingival Hyperplasia. PMID:32256299
• Molecular Genetics & Genomic Medicine • 2018 • 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. PMID:29974678
• Genes • 2024 • Multiple Congenital Anomalies-Hypotonia-Seizures Syndrome 2 Caused by a Novel PIGA Variant Not Associated with a Skewed X-Inactivation Pattern. PMID:38927738

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