Case series and literature review expands phenotypic spectrum of germline PIGA variants

BackgroundDiseases associated with the germline PIGA gene include multiple congenital anomalies-hypotonia-seizures syndrome 2 (MCAHS2) and neurodevelopmental disorder with epilepsy. The clinical heterogeneity of PIGA-related diseases is extensive, so its diagnosis and treatment remain challenging.MethodsWe identified five germline missense pathogenic/likely pathogenic variants in PIGA across six unrelated families (NM_002641.3, c.130C>T p.P44S, c.368C>T p.T123M, c.241C>T p.R81C, c.751T>C p.C251R, and c.985G>T p.V329L), of which three variants have not been reported previously.ResultsIn all probands, the clinical symptoms included early-onset epilepsy, hypotonia, dysmorphic features, and variable congenital anomalies. A literature review of 107 cases supports reclassification of the phenotypic spectrum into severe (15.9%), intermediate (72.0%), and milder (12.1%) categories. Notably, the phenotypes of the five cases were classified as severe (n = 2) or milder (n = 3), consistent with prior reports, but revealed population-specific traits such as universal febrile sensitivity and normal serum alkaline phosphatase levels that are in contrast to elevated levels often noted in Western cohorts. The three children with the milder phenotype were found to have pathogenic/likely pathogenic variants located in exon 2, while the two severe phenotypes showed these variants located in exons 3 and 5.ConclusionOverall, we report three novel pathogenic/likely pathogenic variants that expand clinicians’ understanding of the genetic diversity within this phenotypic spectrum. These insights are expected to be valuable for future pathogenic/likely pathogenic variant analysis and accurate classification of clinical subtypes, which would help improve the understanding of PIGA-related diseases. In addition, our research contributes to ongoing efforts to elucidate the underlying molecular mechanisms and inform precision medicine approaches for affected individuals.