PIGA variants are associated with focal epilepsy with favorable outcome and the sub-molecular effect

The PIGA gene plays a critical role in glycosylphosphatidylinositol (GPI) biosynthesis. PIGA variants have been linked to multiple congenital anomalies-hypotonia-seizures syndrome 2. While epilepsy is a common manifestation and patients usually show developmental delay, it is unclear whether PIGA variants are associated with pure epilepsy.

Trio-based whole-exome sequencing was performed on individuals with focal epilepsy from the China Epilepsy Gene 1.0 project. The sub-molecular effect, damaging effect of the variants, and spatial-temporal expression of PIGA were analyzed to explore its role in epilepsy.

Six PIGA variants were identified in seven unrelated cases with focal epilepsy. In one family, the variant co-segregated with two affected males. All the variants were inherited from the asymptomatic mothers, consistent with an X-linked recessive inheritance pattern. Five of the variants were absent in the general population and one variant had extremely low frequencies. These variants were predicted to be damaging by commonly used in silico tools. Four cases presented with developmental delay and three showed normal development. Further analysis revealed that variants associated with a severe phenotype were located within the GPI biosynthesis domain, whereas variants associated with focal epilepsy and a favorable outcome were outside functional domains, suggesting a sub-molecular effect. Patients with more severe phenotype also had variants with higher damaging scores, indicating a potential genotype-phenotype correlation. PIGA was highly expressed at the embryoid stage, decreased after birth, and then increased again during infancy and the juvenile stage, consistent with the onset age of the patients.

PIGA variants are potentially associated with focal epilepsy with favorable outcome. The sub-molecular effect helps explain phenotype variations.