Biallelic and monoallelic variants in PLXNA1 are implicated in a novel neurodevelopmental disorder with variable cerebral and eye anomalies - Sorbonne Université Access content directly
Journal Articles Genetics in Medicine Year : 2021

Biallelic and monoallelic variants in PLXNA1 are implicated in a novel neurodevelopmental disorder with variable cerebral and eye anomalies

Jeshurun C Kalanithy
  • Function : Author
Enrico Mingardo
  • Function : Author
Haktan B Erdem
  • Function : Author
Zeynep C Akdemir
  • Function : Author
Ender Karaca
  • Function : Author
Tadahiro Mitani
  • Function : Author
Dana Marafi
  • Function : Author
Jawid M Fatih
  • Function : Author
Shalini N Jhangiani
  • Function : Author
Jill V Hunter
  • Function : Author
Tikam Chand Dakal
  • Function : Author
Bhanupriya Dhabhai
  • Function : Author
Omar Dabbagh
  • Function : Author
Hessa S Alsaif
  • Function : Author
Fowzan S Alkuraya
  • Function : Author
Reza Maroofian
  • Function : Author
Henry Houlden
  • Function : Author
Stephanie Efthymiou
  • Function : Author
Natalia Dominik
  • Function : Author
Vincenzo Salpietro
  • Function : Author
Tipu Sultan
  • Function : Author
Shahzad Haider
  • Function : Author
Farah Bibi
  • Function : Author
Holger Thiele
  • Function : Author
Julia Hoefele
  • Function : Author
Korbinian M Riedhammer
  • Function : Author
Matias Wagner
  • Function : Author
Ilaria Guella
  • Function : Author
Michelle Demos
  • Function : Author
Julien Buratti
  • Function : Author
Perrine Charles
  • Function : Author
Elise Valkanas
  • Function : Author
Leigh B Waddell
  • Function : Author
Kristi J Jones
  • Function : Author
Emily C Oates
  • Function : Author
Sandra T Cooper
  • Function : Author
Daniel Macarthur
  • Function : Author
Steffen Syrbe
  • Function : Author
Andreas Ziegler
  • Function : Author
Konrad Platzer
  • Function : Author
Volkan Okur
  • Function : Author
Wendy K Chung
  • Function : Author
Sarah A O’shea
  • Function : Author
Roy Alcalay
  • Function : Author
Stanley Fahn
  • Function : Author
Paul R Mark
  • Function : Author
Renzo Guerrini
  • Function : Author
Annalisa Vetro
  • Function : Author
Beth Hudson
  • Function : Author
Rhonda E Schnur
  • Function : Author
George E Hoganson
  • Function : Author
Jennifer E Burton
  • Function : Author
Meriel Mcentagart
  • Function : Author
Tobias Lindenberg
  • Function : Author
Öznur Yilmaz
  • Function : Author
Benjamin Odermatt
  • Function : Author
Davut Pehlivan
  • Function : Author
Jennifer E Posey
  • Function : Author
James R Lupski
  • Function : Author
Heiko Reutter
  • Function : Author

Abstract

Purpose: To investigate the effect of PLXNA1 variants on the phenotype of patients with autosomal dominant and recessive inheritance patterns and to functionally characterize the zebrafish homologs plxna1a and plxna1b during development. Methods: We assembled ten patients from seven families with biallelic or de novo PLXNA1 variants. We describe genotype-phenotype correlations, investigated the variants by structural modeling, and used Morpholino knockdown experiments in zebrafish to characterize the embryonic role of plxna1a and plxna1b. Results: Shared phenotypic features among patients include global developmental delay (9/10), brain anomalies (6/10), and eye anomalies (7/10). Notably, seizures were predominantly reported in patients with monoallelic variants. Structural modeling of missense variants in PLXNA1 suggests distortion in the native protein. Our zebrafish studies enforce an embryonic role of plxna1a and plxna1b in the development of the central nervous system and the eye. Conclusion: We propose that different biallelic and monoallelic variants in PLXNA1 result in a novel neurodevelopmental syndrome mainly comprising developmental delay, brain, and eye anomalies. We hypothesize that biallelic variants in the extracellular Plexin-A1 domains lead to impaired dimerization or lack of receptor molecules, whereas monoallelic variants in the intracellular Plexin-A1 domains might impair downstream signaling through a dominant-negative effect.
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Dates and versions

hal-04534524 , version 1 (05-04-2024)

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Gabriel C Dworschak, Jaya Punetha, Jeshurun C Kalanithy, Enrico Mingardo, Haktan B Erdem, et al.. Biallelic and monoallelic variants in PLXNA1 are implicated in a novel neurodevelopmental disorder with variable cerebral and eye anomalies. Genetics in Medicine, 2021, 23, pp.1715 - 1725. ⟨10.1038/s41436-021-01196-9⟩. ⟨hal-04534524⟩
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