Research: Lessons learned from 40 novel PIGA patients and a review of the literature


. 2020 Jun;61(6):1142-1155. doi: 10.1111/epi.16545. Epub 2020 May 26.

Lessons learned from 40 novel PIGA patients and a review of the literature

Allan Bayat 1 2Alexej Knaus 3Manuela Pendziwiat 4Alexandra Afenjar 5Tahsin Stefan Barakat 6Friedrich Bosch 7Bert Callewaert 8 9Patrick Calvas 10Berten Ceulemans 11Nicolas Chassaing 10Christel Depienne 12 13Milda Endziniene 14Carlos R Ferreira 15Carolina Fischinger Moura de Souza 16Cécile Freihuber 17 18Shiva Ganesan 19 20 21Svetlana Gataullina 22 23Renzo Guerrini 24Anne-Marie Guerrot 25Lars Hansen 26Aleksandra Jezela-Stanek 27Caroline Karsenty 28Anneke Kievit 6Frank R Kooy 29Christian M Korff 30Johanne Kragh Hansen 31Martin Larsen 31 32Valérie Layet 33Gaetan Lesca 34 35Kim L McBride 36 37 38Marije Meuwissen 29Cyril Mignot 39 40Martino Montomoli 24Hannah Moore 41Sophie Naudion 42Caroline Nava 40Marie-Christine Nougues 43Elena Parrini 24Matthew Pastore 36 38Jurgen H Schelhaas 44Steven Skinner 41Krzysztoł Szczałuba 45Ashley Thomas 46Mads Thomassen 31 32Lisbeth Tranebjaerg 47 48Marjon van Slegtenhorst 6Lynne A Wolfe 49 50Dennis Lal 51 52 53 54 55Elena Gardella 1 2 56Lilian Bomme Ousager 31 32Tobias Brünger 51Ingo Helbig 4 19 20 21 57Peter Krawitz 3Rikke S Møller 1 2Affiliations expand


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.

Keywords: PIGA; Fryns syndrome phenotype; bioinformatical comparison; genotype-phenotype correlation; mild developmental delay.

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