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

TitleBiallelic and monoallelic variants in PLXNA1 are implicated in a novel neurodevelopmental disorder with variable cerebral and eye anomalies.
Publication TypeJournal Article
Year of Publication2021
AuthorsDworschak, GC, Punetha, J, Kalanithy, JC, Mingardo, E, Erdem, HB, Akdemir, ZC, Karaca, E, Mitani, T, Marafi, D, Fatih, JM, Jhangiani, SN, Hunter, JV, Dakal, TChand, Dhabhai, B, Dabbagh, O, Alsaif, HS, Alkuraya, FS, Maroofian, R, Houlden, H, Efthymiou, S, Dominik, N, Salpietro, V, Sultan, T, Haider, S, Bibi, F, Thiele, H, Hoefele, J, Riedhammer, KM, Wagner, M, Guella, I, Demos, M, Keren, B, Buratti, J, Charles, P, Nava, C, Héron, D, Heide, S, Valkanas, E, Waddell, LB, Jones, KJ, Oates, EC, Cooper, ST, MacArthur, D, Syrbe, S, Ziegler, A, Platzer, K, Okur, V, Chung, WK, O'Shea, SA, Alcalay, R, Fahn, S, Mark, PR, Guerrini, R, Vetro, A, Hudson, B, Schnur, RE, Hoganson, GE, Burton, JE, McEntagart, M, Lindenberg, T, Yilmaz, Ö, Odermatt, B, Pehlivan, D, Posey, JE, Lupski, JR, Reutter, H
JournalGenet Med
Volume23
Issue9
Pagination1715-1725
Date Published2021 09
ISSN1530-0366
KeywordsAnimals, Eye Abnormalities, Genetic Association Studies, Humans, Nerve Tissue Proteins, Neurodevelopmental Disorders, Phenotype, Receptors, Cell Surface, Zebrafish
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.

DOI10.1038/s41436-021-01196-9
Alternate JournalGenet Med
PubMed ID34054129
PubMed Central IDPMC8460429
Grant ListUM1 HG008900 / HG / NHGRI NIH HHS / United States
MR/S005021/1 / MRC_ / Medical Research Council / United Kingdom
R01 HG009141 / HG / NHGRI NIH HHS / United States
UM1 HG006542 / HG / NHGRI NIH HHS / United States
R35 NS105078 / NS / NINDS NIH HHS / United States
K08 HG008986 / HG / NHGRI NIH HHS / United States
MR/S01165X/1 / MRC_ / Medical Research Council / United Kingdom
/ WT_ / Wellcome Trust / United Kingdom
G0601943 / MRC_ / Medical Research Council / United Kingdom