Objective: To define the phenotypic spectrum of phosphatidylinositol glycan class A protein (PIGA)-related congenital disorder of glycosylation (PIGA-CDG) and evaluate genotype-phenotype correlations. Methods: Our cohort encompasses 40 affected males with a pathogenic PIGA variant. We performed a detailed phenotypic assessment, and in addition, we reviewed the available clinical data of 36 previously published cases and assessed the variant pathogenicity using bioinformatical approaches. Results: Most individuals had hypotonia, moderate to profound global developmental delay, and intractable seizures. We found that PIGA-CDG spans from a pure neurological phenotype at the mild end to a Fryns syndrome–like phenotype. We found a high frequency of cardiac anomalies including structural anomalies and cardiomyopathy, and a high frequency of spontaneous death, especially in childhood. Comparative bioinformatical analysis of common variants, found in the healthy population, and pathogenic variants, identified in affected individuals, revealed a profound physiochemical dissimilarity of the substituted amino acids in variant constrained regions of the protein. Significance: Our comprehensive analysis of the largest cohort of published and novel PIGA patients broadens the spectrum of PIGA-CDG. Our genotype-phenotype correlation facilitates the estimation on pathogenicity of variants with unknown clinical significance and prognosis for individuals with pathogenic variants in PIGA.

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Keywords bioinformatical comparison, Fryns syndrome phenotype, genotype-phenotype correlation, mild developmental delay, PIGA
Persistent URL dx.doi.org/10.1111/epi.16545, hdl.handle.net/1765/127515
Journal Epilepsia
Bayat, A. (Allan), Knaus, A. (Alexej), Pendziwiat, M. (Manuela), Afenjar, A, Stefan Barakat, T. (Tahsin), Bosch, F. (Friedrich), … Møller, R.S. (2020). Lessons learned from 40 novel PIGA patients and a review of the literature. Epilepsia. doi:10.1111/epi.16545