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

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningfagfællebedømt

  • 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
  • Aleksandra 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
  • Marjon van Slegtenhorst
  • Lynne A. Wolfe
  • Dennis Lal
  • Elena Gardella
  • Lilian Bomme Ousager
  • Tobias Brünger
  • Ingo Helbig
  • Peter Krawitz
  • Rikke S. Møller

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
TidsskriftEpilepsia
ISSN0013-9580
DOI
StatusAccepteret/In press - 2020

ID: 243008487