Submission Details

PIGA was first reported in relation to X-linked complex neurodevelopmental disorder in 2012 (Johnston et al., PMID: 22305531). Pathogenic variants in PIGA result in a glycosyphosphatidylinositol (GPI) anchor protein defect, leading to a congenital disorder of glycosylation (CDG). The most common clinical presentation is infantile-onset developmental and epileptic encephalopathy with seizures that are refractory to treatment, myoclonus, hypotonia, severe to profound intellectual disability, characteristic facial features, and brain abnormalities (PMID: 32452540, 25885527). Liver, renal, and/or cardiac involvement, elevated alkaline phosphatase, ichthyosis or other skin manifestations, and systemic iron overload have been described in some patients, and early death can occur. Some individuals have a less severe clinical presentation consisting of mild to severe intellectual disability, developmental delay, and treatment-responsive seizures in the absence of involvement of other organs (PMID: 32452540, 25885527).

Per criteria outlined by the ClinGen Lumping and Splitting Working Group, we found no difference in molecular mechanism, inheritance pattern, or phenotypic variability to support splitting the curation into different diseases. Therefore, the following disease entities have been lumped into one disease entity: multiple congenital anomalies-hypotonia-seizures syndrome 2 (OMIM: 300868, ORPHA:300496), malignant migrating focal seizures of infancy (ORPHA:293181), infantile epileptic spasms syndrome (ORPHA:3451), ferro-cerebro-cutaneous syndrome (ORPHA:397922), and neurodevelopmental disorder with epilepsy and hemochromatosis (OMIM: 301072). This curation does not address the association of somatic variants in PIGA with paroxysmal nocturnal hemoglobinuria (OMIM: 300818).

The ClinGen Epilepsy GCEP opted to curate this gene for complex neurodevelopmental disorder (MONDO:0100038) rather than congenital disorder of glycosylation (MONDO:0015286) to convey the specific phenotype of reported patients rather than curating for a more generic term (referring to a large group of disorders that can often only be diagnosed after the specific genetic etiology is known and are associated with a broad, nonspecific phenotypic spectrum.)

This curation includes more than 25 missense, nonsense, and frameshift variants reported in over 40 probands from 22 publications (PMIDs: 22305531, 24706016, 24259184, 24357517, 24259288, 25326635, 25885527, 25473036, 26545172, 26545172, 26993267, 27126216, 26923721, 29656098, 29414593, 29502866, 29974678, 28133863, 32452540, 32694024, 34875027, 36324500). More evidence is available in the literature, but the maximum score for genetic evidence (12 pts.) has been reached. The mechanism of pathogenicity is partial loss of function of an enzyme that is part of a complex that catalyzes the first step of GPI-anchor protein biosynthesis, and truncating variants are hypomorphic (PMID: 32452540). The gene-disease relationship is also supported by animal models (PMIDs: 37961693).

In summary, there is definitive evidence supporting the relationship between PIGA and X-linked complex neurodevelopmental disorder. This has been repeatedly demonstrated in both the research and clinical diagnostic settings and has been upheld over time. This classification was approved by the ClinGen Epilepsy GCEP on the meeting date April 16, 2024 (SOP Version 10).

This gene-disease pair was originally evaluated by the ClinGen Epilepsy GCEP on April 25, 2019. In 2024, the GCEP added several new papers and patients. As a result of this reevaluation, the classification changed from moderate to definitive.