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Dworschak, G.C.* ; Punetha, J.* ; Kalanithy, J.C.* ; Mingardo, E.* ; Erdem, H.B.* ; Akdemir, Z.C.* ; Karaca, E.* ; Mitani, T.* ; Marafi, D.* ; Fatih, J.M.* ; Jhangiani, S.N.* ; Hunter, J.V.* ; Dakal, T.C.* ; Dhabhai, B.* ; Dabbagh, O.* ; Alsaif, H.S.* ; Alkuraya, F.S.* ; Maroofian, R.* ; Houlden, H.* ; Efthymiou, S.* ; Dominik, N.* ; Salpietro,V.* ; Sultan, T.* ; Haider, S.* ; Bibi, F.* ; Thiele, H.* ; Hoefele, J.* ; Riedhammer, K.M.* ; Wagner, M. ; Guella, I.* ; Demos, M.* ; Keren, B.* ; Buratti, J.* ; Charles, P.* ; Nava, C.* ; Heron, D.* ; Heide, S.* ; Valkanas, E.* ; Waddell, L.B.* ; Jones, K.J.* ; Oates, E.C.* ; Cooper, S.T.* ; MacArthur, D.* ; Syrbe, S.* ; Ziegler, A.* ; Platzer, K.* ; Okur, V.* ; Chung, W.K.* ; O'Shea, S.A.* ; Alcalay, R.* ; Fahn, S.* ; Mark, P.R.* ; Guerrini, R.* ; Vetro, A.* ; Hudson, B.* ; Schnur, R.E.* ; Hoganson, G.E.* ; Burton, J.E.* ; McEntagart, M.* ; Lindenberg, T.* ; Yilmaz, Ö.* ; Odermatt, B.* ; Pehlivan, D.* ; Posey, J.E.* ; Lupski, J.R.* ; Reutter, H.*

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

Genet. Med. 23, 1715–1725 (2021)
Postprint Research data DOI PMC
Open Access Gold (Paid Option)
Creative Commons Lizenzvertrag
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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Publication type Article: Journal article
Document type Scientific Article
Corresponding Author
Keywords De-novo Mutations; Plexina1; Expression; Proteins; Receptor; Family
ISSN (print) / ISBN 1530-0366
e-ISSN 1098-3600
Journal Genetics in Medicine
Quellenangaben Volume: 23, Issue: , Pages: 1715–1725 Article Number: , Supplement: ,
Publisher Lippincott Williams & Wilkins
Publishing Place Baltimore, Md.
Non-patent literature Publications
Reviewing status Peer reviewed
Institute(s) Institute of Neurogenomics (ING)
Grants Deutsche Forschungsgemeinschaft