Biallelic variants in CELSR1 cause brain malformations, neurodevelopmental disorders and epilepsy in humans

The CELSR1 gene is a core component of the tissue/planar cell polarity signaling pathway. It encodes a developmentally regulated protein that belongs to the adhesion G protein-coupled receptors. Herein we describe seven subjects, from five unrelated families, featuring a neurodevelopmental disorder associated with biallelic CELSR1 variants. The main phenotypic features of this disorder are different types of brain malformations (including pachygyria, periventricular nodular heterotopia, abnormal corpus callosum, white matter abnormalities, hypoplasia of brainstem and cerebellum), variable degrees of neurodevelopmental delay and intellectual disability, behavioral disorders, and, in some subjects, epilepsy. Using whole exome sequencing, we identify five compound heterozygous variants and one homozygous variant of CELSR1 in these subjects. We infer the pathogenicity and functional effects of these variants through bioinformatic analysis, protein modelling and prediction tools. To further characterize the effects of mutant CELSR1, we generate Celsr1 knockout mice, which exhibit partial agenesis of the corpus callosum, periventricular heterotopia and irregular shape of the ventricular/subventricular zone, enlarged lateral ventricles with a fully penetrant phenotype, and increased susceptibility to seizures. These findings emphasize the importance of CELSR1 in several polarity-dependent processes during embryonic and postnatal development.

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Journal
Nature Communications
Published
2026-01-13
DOI
https://doi.org/10.1038/s41467-025-67576-w
Citations
2
Primary Topic
Wnt/β-catenin signaling in development and cancer
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article
Field-Weighted Citation Impact
44.47

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article

Biallelic variants in CELSR1 cause brain malformations, neurodevelopmental disorders and epilepsy in humans

Monica H. Wojcik, Trine Bjørg Hammer, Christina Fenger, Klaus Brusgaard et al.
2 citations
Nature Communications
Wnt/β-catenin signaling in development and cancer
44.47
article

Biallelic variants in CELSR1 cause brain malformations, neurodevelopmental disorders and epilepsy in humans

Monica H. Wojcik, Trine Bjørg Hammer, Christina Fenger, Klaus Brusgaard, Birgit Jepsen, Claudia Bonardi, Monika Bekiesińska‐Figatowska, Mateusz Dawidziuk, Fadel Tissir, Camilla Gøbel Madsen, Evan Gouy, Sara Cabet, Guido Rubboli, Gaetan Lesca, Pawel Gawlinski, Guoliang Chai, Wojciech Wiszniewski, Pilvi Ilves, Massimiliano Rossi, Mohamed Aittaleb, Allan Bayat, Elena Gardella, Nuria Ruiz-Reig, Tomasz S. Mieszczanek, Rikke S. Møller, Katrin Õunap
article en
2 citations

Abstract

The CELSR1 gene is a core component of the tissue/planar cell polarity signaling pathway. It encodes a developmentally regulated protein that belongs to the adhesion G protein-coupled receptors. Herein we describe seven subjects, from five unrelated families, featuring a neurodevelopmental disorder associated with biallelic CELSR1 variants. The main phenotypic features of this disorder are different types of brain malformations (including pachygyria, periventricular nodular heterotopia, abnormal corpus callosum, white matter abnormalities, hypoplasia of brainstem and cerebellum), variable degrees of neurodevelopmental delay and intellectual disability, behavioral disorders, and, in some subjects, epilepsy. Using whole exome sequencing, we identify five compound heterozygous variants and one homozygous variant of CELSR1 in these subjects. We infer the pathogenicity and functional effects of these variants through bioinformatic analysis, protein modelling and prediction tools. To further characterize the effects of mutant CELSR1, we generate Celsr1 knockout mice, which exhibit partial agenesis of the corpus callosum, periventricular heterotopia and irregular shape of the ventricular/subventricular zone, enlarged lateral ventricles with a fully penetrant phenotype, and increased susceptibility to seizures. These findings emphasize the importance of CELSR1 in several polarity-dependent processes during embryonic and postnatal development.

Nature CommunicationsVol. 17(1)
Université Claude Bernard Lyon 1 (FR), Broad Institute (US), Boston Children's Hospital (US), Centre National de la Recherche Scientifique (FR), University of Padua (IT), Emory University (US), Inserm (FR), Oregon Health & Science University (US), University of Southern Denmark (DK), Capital Medical University (CN), Odense University Hospital (DK), Hvidovre Hospital (DK), Tartu University Hospital (EE), Copenhagen University Hospital (DK), Rigshospitalet (DK), Hôpital Femme Mère Enfant (FR), Centre de Recherche en Neurosciences de Lyon (FR), Hospices Civils de Lyon (FR), Institut NeuroMyoGène (FR), Epilepsy Action (GB), Hamad bin Khalifa University (QA), Filadelfia (DK), Broad Center (US), University of Tartu (EE), UCLouvain (BE)
Broad Institute, Eesti Teadusagentuur, Fonds De La Recherche Scientifique - FNRS, Fonds Wetenschappelijk Onderzoek, Fondation Médicale Reine Elisabeth, National Heart, Lung, and Blood Institute
Good health and well-being
Openalex Percentile: Top 0%
Wnt/β-catenin signaling in development and cancer
44.47
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