PIGA – Ferro-Cerebro-Cutaneous Syndrome

The PIGA gene encodes the phosphatidylinositol glycan anchor biosynthesis class A protein, a catalytic subunit essential for the first step of glycosylphosphatidylinositol (GPI) anchor assembly. Germline mutations in PIGA have been implicated in a spectrum of X-linked disorders, including multiple congenital anomalies-hypotonia-seizures syndrome 2 (MCAHS2) and ferro-cerebro-cutaneous syndrome (MONDO:0018346). Ferro-cerebro-cutaneous syndrome features early-onset epileptic encephalopathy, systemic iron overload, and cutaneous manifestations, reflecting multisystem GPI-anchor deficiency.

A landmark study identified the recurrent truncating variant c.1234C>T (p.Arg412Ter) in PIGA in four affected males: three individuals from two unrelated families and a fetus from the original Simpson-Golabi-Behmel syndrome type 2 pedigree, all presenting with overlapping clinical features (PMID:26545172). This hypomorphic variant segregates with disease in an X-linked recessive manner and recurs in unrelated pedigrees, underscoring its pathogenicity.

Inheritance is X-linked recessive, with hemizygous males fully manifesting the phenotype; carrier females are typically unaffected due to X-inactivation. To date, 4 probands across 3 unrelated families have been reported with this identical truncating variant, with no additional affected relatives beyond these index cases.

Affected males consistently exhibit early-onset intractable epileptic encephalopathy, generalized hypotonia, macrocephaly, coarse facial features, wide mouth, gingival overgrowth, and micropenis. Structural brain anomalies and increased birth weight are also common, reflecting the systemic impact of GPI-anchor disruption.

Mechanistically, c.1234C>T introduces a premature stop that truncates the C-terminal region of PIGA, abrogating its glycosyltransferase activity. Structural and functional analyses of PIG-A have delineated critical domains required for GPI-anchor assembly, with in vitro mutagenesis confirming that disruption of key residues severely impairs enzyme function (PMID:9398536). This loss-of-function mechanism aligns with the clinical severity observed.

Integration of genetic and experimental data yields a Strong gene–disease association. The recurrent nature of a truncating PIGA variant in multiple families, combined with well-established functional impact, supports robust clinical validity. Key take-home: screening for the c.1234C>T (p.Arg412Ter) PIGA variant is critical for the accurate diagnosis of ferro-cerebro-cutaneous syndrome and enables informed genetic counseling.

References

• American journal of medical genetics. Part A • 2016 • A recurrent germline mutation in the PIGA gene causes Simpson-Golabi-Behmel syndrome type 2. PMID:26545172
• Blood cells, molecules & diseases • 1997 • Structural and functional analysis of the Pig-a protein that is mutated in paroxysmal nocturnal hemoglobinuria. PMID:9398536

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