Dataset Information

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

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.

SUBMITTER: Dworschak GC

PROVIDER: S-EPMC8460429 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Publications

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

Dworschak Gabriel C GC Punetha Jaya J Kalanithy Jeshurun C JC Mingardo Enrico E Erdem Haktan B HB Akdemir Zeynep C ZC Karaca Ender E Mitani Tadahiro T Marafi Dana D Fatih Jawid M JM Jhangiani Shalini N SN Hunter Jill V JV Dakal Tikam Chand TC Dhabhai Bhanupriya B Dabbagh Omar O Alsaif Hessa S HS Alkuraya Fowzan S FS Maroofian Reza R Houlden Henry H Efthymiou Stephanie S Dominik Natalia N Salpietro Vincenzo V Sultan Tipu T Haider Shahzad S Bibi Farah F Thiele Holger H Hoefele Julia J Riedhammer Korbinian M KM Wagner Matias M Guella Ilaria I Demos Michelle M Keren Boris B Buratti Julien J Charles Perrine P Nava Caroline C Héron Delphine D Heide Solveig S Valkanas Elise E Waddell Leigh B LB Jones Kristi J KJ Oates Emily C EC Cooper Sandra T ST MacArthur Daniel D Syrbe Steffen S Ziegler Andreas A Platzer Konrad K Okur Volkan V Chung Wendy K WK O'Shea Sarah A SA Alcalay Roy R Fahn Stanley S Mark Paul R PR Guerrini Renzo R Vetro Annalisa A Hudson Beth B Schnur Rhonda E RE Hoganson George E GE Burton Jennifer E JE McEntagart Meriel M Lindenberg Tobias T Yilmaz Öznur Ö Odermatt Benjamin B Pehlivan Davut D Posey Jennifer E JE Lupski James R JR Reutter Heiko H

Genetics in medicine : official journal of the American College of Medical Genetics 20210530 9

<h4>Purpose</h4>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.<h4>Methods</h4>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 t ...[more]

PMID: 34054129

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Dataset Information

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

Purpose

Methods

Results

Conclusion

Publications

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

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