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

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

doi:10.1038/s41436-021-01196-9

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

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

Gabriel C Dworschak, Jaya Punetha, Jeshurun C Kalanithy, Enrico Mingardo, Haktan B Erdem, Zeynep C Akdemir, Ender Karaca, Tadahiro Mitani, Dana Marafi, Jawid M Fatih, …

Genetics in medicine, Vol.23(9), pp.1715-1725

01/09/2021

DOI: https://doi.org/10.1038/s41436-021-01196-9

PMID: 34054129

Abstract

Animals

Eye Abnormalities - genetics

Genetic Association Studies

Humans

Nerve Tissue Proteins - genetics

Neurodevelopmental Disorders - genetics

Phenotype

Receptors, Cell Surface

Zebrafish - genetics

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. 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. 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. 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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Title: Biallelic and monoallelic variants in PLXNA1 are implicated in a novel neurodevelopmental disorder with variable cerebral and eye anomalies
Creators - without role: Gabriel C Dworschak - University of Bonn
Jaya Punetha - Icahn School of Medicine at Mount Sinai
Jeshurun C Kalanithy - University of Bonn
Enrico Mingardo - University of Bonn
Haktan B Erdem - Ankara
Zeynep C Akdemir - Baylor College of Medicine
Ender Karaca - University of Alabama at Birmingham
Tadahiro Mitani - Baylor College of Medicine
Dana Marafi - Baylor College of Medicine
Jawid M Fatih - Baylor College of Medicine
Shalini N Jhangiani - Baylor Genetics
Jill V Hunter - Baylor College of Medicine
Tikam Chand Dakal - Mohanlal Sukhadia University
Bhanupriya Dhabhai - Mohanlal Sukhadia University
Omar Dabbagh - King Faisal Specialist Hospital & Research Centre
Hessa S Alsaif - King Faisal Specialist Hospital & Research Centre
Fowzan S Alkuraya - King Faisal Specialist Hospital & Research Centre
Reza Maroofian - National Hospital for Neurology and Neurosurgery
Henry Houlden - National Hospital for Neurology and Neurosurgery
Stephanie Efthymiou - University College London
Natalia Dominik - University College London
Vincenzo Salpietro - University College London
Tipu Sultan - Department of Pediatric Neurology, Institute of Child Health, The Children’s Hospital Lahore Lahore Pakistan
Shahzad Haider - Rawalpindi Medical University
Farah Bibi - Pir Mehr Ali Shah Arid Agriculture University
Holger Thiele - University of Cologne
Julia Hoefele - Rechts der Isar Hospital
Korbinian M Riedhammer - Rechts der Isar Hospital
Matias Wagner - Rechts der Isar Hospital
Ilaria Guella - University of British Columbia
Michelle Demos - British Columbia Children's Hospital
Boris Keren - Pitié-Salpêtrière Hospital
Julien Buratti - Pitié-Salpêtrière Hospital
Perrine Charles - Pitié-Salpêtrière Hospital
Caroline Nava - Pitié-Salpêtrière Hospital
Delphine Héron - Pitié-Salpêtrière Hospital
Solveig Heide - Pitié-Salpêtrière Hospital
Elise Valkanas - Broad Institute
Leigh B Waddell - University of Sydney
Kristi J Jones - University of Sydney
Emily C Oates - UNSW Sydney
Sandra T Cooper - Children's Medical Research Institute
Daniel MacArthur - Massachusetts General Hospital
Steffen Syrbe - University Hospital Heidelberg
Andreas Ziegler - University Hospital Heidelberg
Konrad Platzer - Leipzig University
Volkan Okur - Columbia University
Wendy K Chung - Columbia University
Sarah A O'Shea - Columbia University
Roy Alcalay - Columbia University
Stanley Fahn - Columbia University
Paul R Mark - Helen DeVos Children's Hospital
Renzo Guerrini - Meyer Children's Hospital
Annalisa Vetro - Meyer Children's Hospital
Beth Hudson - GeneDx Gaithersburg MD USA
Rhonda E Schnur - GeneDx Gaithersburg MD USA
George E Hoganson - Illinois College
Jennifer E Burton - University of Illinois Urbana-Champaign
Meriel McEntagart - South West London and St George's Mental Health NHS Trust
Tobias Lindenberg - University of Bonn
Öznur Yilmaz - University of Bonn
Benjamin Odermatt - University of Bonn
Davut Pehlivan - Baylor College of Medicine
Jennifer E Posey - Baylor College of Medicine
James R Lupski - Baylor College of Medicine
Heiko Reutter - University of Bonn
Publication Details: Genetics in medicine, Vol.23(9), pp.1715-1725
Grant note: UM1 HG008900 / NHGRI NIH HHS G0601943 / Medical Research Council MR/S005021/1 / Medical Research Council Wellcome Trust R35 NS105078 / NINDS NIH HHS UM1 HG006542 / NHGRI NIH HHS UL1 TR001863 / NCATS NIH HHS R01 HG009141 / NHGRI NIH HHS MR/S01165X/1 / Medical Research Council K08 HG008986 / NHGRI NIH HHS
Identifiers: 9918661408331
Academic Unit: King Faisal University; King Abdulaziz City for Science & Technology; King Khalid University; King Saud University; Alfaisal University
Language: English
Resource Type: Journal article