TY - JOUR

T1 - Lessons learned from 40 novel PIGA patients and a review of the literature

AU - Bayat, Allan

AU - Knaus, Alexej

AU - Pendziwiat, Manuela

AU - Afenjar, Alexandra

AU - Stefan Barakat, Tahsin

AU - Bosch, Friedrich

AU - Callewaert, Bert

AU - Calvas, Patrick

AU - Ceulemans, Berten

AU - Chassaing, Nicolas

AU - Depienne, Christel

AU - Endziniene, Milda

AU - Ferreira, Carlos R.

AU - Moura de Souza, Carolina Fischinger

AU - Freihuber, Cécile

AU - Ganesan, Shiva

AU - Gataullina, Svetlana

AU - Guerrini, Renzo

AU - Guerrot, Anne Marie

AU - Hansen, Lars

AU - Jezela-Stanek, Aleksandra

AU - Karsenty, Caroline

AU - Kievit, Anneke

AU - Kooy, Frank R.

AU - Korff, Christian M.

AU - Kragh Hansen, Johanne

AU - Larsen, Martin

AU - Layet, Valérie

AU - Lesca, Gaetan

AU - McBride, Kim L.

AU - Meuwissen, Marije

AU - Mignot, Cyril

AU - Montomoli, Martino

AU - Moore, Hannah

AU - Naudion, Sophie

AU - Nava, Caroline

AU - Nougues, Marie Christine

AU - Parrini, Elena

AU - Pastore, Matthew

AU - Schelhaas, Jurgen H.

AU - Skinner, Steven

AU - Szczałuba, Krzysztoł

AU - Thomas, Ashley

AU - Thomassen, Mads

AU - Tranebjærg, Lisbeth

AU - van Slegtenhorst, Marjon

AU - Wolfe, Lynne A.

AU - Lal, Dennis

AU - Gardella, Elena

AU - Bomme Ousager, Lilian

AU - Brünger, Tobias

AU - Helbig, Ingo

AU - Krawitz, Peter

AU - Møller, Rikke S.

PY - 2020

Y1 - 2020

N2 - 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.

AB - 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.

KW - bioinformatical comparison

KW - Fryns syndrome phenotype

KW - genotype-phenotype correlation

KW - mild developmental delay

KW - PIGA

U2 - 10.1111/epi.16545

DO - 10.1111/epi.16545

M3 - Journal article

C2 - 32452540

AN - SCOPUS:85085585320

VL - 61

SP - 1142

EP - 1155

JO - Epilepsia

JF - Epilepsia

SN - 0013-9580

IS - 6

ER -