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

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

Publikation: Bidrag til tidsskriftReviewForskningpeer review

Abstrakt

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.

OriginalsprogEngelsk
Sider (fra-til)1142-1155
Antal sider14
TidsskriftEpilepsia
Vol/bind61
Udgave nummer6
Tidlig onlinedato26 maj 2020
DOI
StatusUdgivet - jun. 2020

Bibliografisk note

© 2020 International League Against Epilepsy.

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