Lessons learned from 40 novel PIGA patients and a review of the literature.
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Bayat Allan, Knaus Alexej, Pendziwiat Manuela, Afenjar Alexandra, Barakat Tahsin Stefan, Bosch Friedrich, Callewaert Bert, Calvas Patrick, Ceulemans Berten, Chassaing Nicolas, Depienne Christel, Endziniene Milda, Ferreira Carlos R, Moura de Souza Carolina Fischinger, Freihuber Cécile, Ganesan Shiva, Gataullina Svetlana, Guerrini Renzo, Guerrot Anne-Marie, Hansen Lars, Jezela-Stanek Aleksandra, Karsenty Caroline, Kievit Anneke, Kooy Frank R, Korff Christian M, Kragh Hansen Johanne, Larsen Martin, Layet Valérie, Lesca Gaetan, McBride Kim L, Meuwissen Marije, Mignot Cyril, Montomoli Martino, Moore Hannah, Naudion Sophie, Nava Caroline, Nougues Marie-Christine, Parrini Elena, Pastore Matthew, Schelhaas Jurgen H, Skinner Steven, Szczałuba Krzysztoł, Thomas Ashley, Thomassen Mads, Tranebjaerg Lisbeth, van Slegtenhorst Marjon, Wolfe Lynne A, Lal Dennis, Gardella Elena, Bomme Ousager Lilian, Brünger Tobias, Helbig Ingo, Krawitz Peter, Møller Rikke S
Аннотация
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.