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<p>The <i>CELSR1</i> 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 <i>CELSR1</i> 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 <i>CELSR1</i> 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 <i>CELSR1</i>, 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&#xa0;importance of <i>CELSR1</i> in several polarity-dependent processes during embryonic and postnatal development.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月13日

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  • Claudia M. Bonardi,
  • Rikke S. Møller,
  • Nuria Ruiz-Reig,
  • Guoliang Chai,
  • Camilla G. Madsen,
  • Allan Bayat,
  • Trine B. Hammer,
  • Christina D. Fenger,
  • Elena Gardella,
  • Pawel Gawlinski,
  • Mateusz Dawidziuk,
  • Wojciech Wiszniewski,
  • Monika Bekiesinska-Figatowska,
  • Sara Cabet,
  • Massimiliano Rossi,
  • Gaetan Lesca,
  • Evan Gouy,
  • Birgit Jepsen,
  • Tomasz S. Mieszczanek,
  • Rossana Sanchez Russo,
  • Eileen E. Barr,
  • Katrin Õunap,
  • Pilvi Ilves,
  • Monica H. Wojcik,
  • Mohamed Aittaleb,
  • Klaus Brusgaard,
  • Fadel Tissir,
  • Guido Rubboli

摘要

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.