|Publication Type||Journal Article|
|Year of Publication||2020|
|Authors||Bayat, A, Knaus, A, Pendziwiat, M, Afenjar, A, Barakat, TStefan, Bosch, F, Callewaert, B, Calvas, P, Ceulemans, B, Chassaing, N, Depienne, C, Endziniene, M, Ferreira, CR, de Souza, CFischinger, Freihuber, C, Ganesan, S, Gataullina, S, Guerrini, R, Guerrot, A-M, Hansen, L, Jezela-Stanek, A, Karsenty, C, Kievit, A, Kooy, FR, Korff, CM, Hansen, JKragh, Larsen, M, Layet, V, Lesca, G, McBride, KL, Meuwissen, M, Mignot, C, Montomoli, M, Moore, H, Naudion, S, Nava, C, Nougues, M-C, Parrini, E, Pastore, M, Schelhaas, JH, Skinner, S, Szczałuba, K, Thomas, A, Thomassen, M, Tranebjaerg, L, van Slegtenhorst, M, Wolfe, LA, Lal, D, Gardella, E, Ousager, LBomme, Brünger, T, Helbig, I, Krawitz, P, Møller, RS|
|Date Published||2020 May 26|
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.
|Grant List||PPRC-2018-50 / / European Academy of Dermatology and Venereology / |
BOF-Start 01N04516 / / Ghent University /
FP7/2007-2013 / / European Union Seventh Framework Program /
/ / University of Kiel /
HE 5415/5-1 / / German Research Foundation /
HE 5415/6-1 / / German Research Foundation /
FOR2715 HE5415/7-1 / / German Research Foundation /
9161702 / / Netherlands Organization for Scientific Research /
/ / Brain & Behavior Research Foundation /
DNRF107 / / Danish National Research Foundation /