Epilepsia

. 2020 Jun;61(6):1142-1155. doi: 10.1111/epi.16545. Epub 2020 May 26.https://pubmed.ncbi.nlm.nih.gov/32452540/

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

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

• PMID: 32452540
• DOI: 10.1111/epi.16545

Abstract

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.

© 2020 International League Against Epilepsy.