PUBLICATION
Biallelic and monoallelic variants in PLXNA1 are implicated in a novel neurodevelopmental disorder with variable cerebral and eye anomalies
- Authors
- 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., Héron, 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.
- ID
- ZDB-PUB-210601-8
- Date
- 2021
- Source
- Genetics in medicine : official journal of the American College of Medical Genetics 23(9): 1715-1725 (Journal)
- Registered Authors
- Odermatt, Benjamin
- Keywords
- none
- MeSH Terms
-
- Animals
- Eye Abnormalities*/genetics
- Genetic Association Studies
- Humans
- Nerve Tissue Proteins/genetics
- Neurodevelopmental Disorders*/genetics
- Phenotype
- Receptors, Cell Surface
- Zebrafish/genetics
- PubMed
- 34054129 Full text @ Genet. Med.
Citation
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., Héron, 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. (2021) Biallelic and monoallelic variants in PLXNA1 are implicated in a novel neurodevelopmental disorder with variable cerebral and eye anomalies. Genetics in medicine : official journal of the American College of Medical Genetics. 23(9):1715-1725.
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.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping