Dataset Information

CUX1-related neurodevelopmental disorder: deep insights into phenotype-genotype spectrum and underlying pathology.

ABSTRACT: Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a Cux1^+/- mouse model. Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished individuals). We analyze brain CUX1 expression and susceptibility to epilepsy in Cux1^+/- mice. We describe 34 individuals, from which 30 were unrelated, with 26 different null and four missense variants. The leading symptoms were mild to moderate delayed speech and motor development and borderline to moderate intellectual disability. Additional symptoms were muscular hypotonia, seizures, joint laxity, and abnormalities of the forehead. In Cux1^+/- mice, we found delayed growth, histologically normal brains, and increased susceptibility to seizures. In Cux1^+/- brains, the expression of Cux1 transcripts was half of WT animals. Expression of CUX1 proteins was reduced, although in early postnatal animals significantly more than in adults. In summary, disease-causing CUX1 variants result in a non-syndromic phenotype of developmental delay and intellectual disability. In some individuals, this phenotype ameliorates with age, resulting in a clinical catch-up and normal IQ in adulthood. The post-transcriptional balance of CUX1 expression in the heterozygous brain at late developmental stages appears important for this favorable clinical course.

SUBMITTER: Oppermann H

PROVIDER: S-EPMC10620399 | biostudies-literature | 2023 Nov

REPOSITORIES: biostudies-literature

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CUX1-related neurodevelopmental disorder: deep insights into phenotype-genotype spectrum and underlying pathology.

Oppermann Henry H Marcos-Grañeda Elia E Weiss Linnea A LA Gurnett Christina A CA Jelsig Anne Marie AM Vineke Susanne H SH Isidor Bertrand B Mercier Sandra S Magnussen Kari K Zacher Pia P Hashim Mona M Pagnamenta Alistair T AT Race Simone S Srivastava Siddharth S Frazier Zoë Z Maiwald Robert R Pergande Matthias M Milani Donatella D Rinelli Martina M Levy Jonathan J Krey Ilona I Fontana Paolo P Lonardo Fortunato F Riley Stephanie S Kretzer Jasmine J Rankin Julia J Reis Linda M LM Semina Elena V EV Reuter Miriam S MS Scherer Stephen W SW Iascone Maria M Weis Denisa D Fagerberg Christina R CR Brasch-Andersen Charlotte C Hansen Lars Kjaersgaard LK Kuechler Alma A Noble Nathan N Gardham Alice A Tenney Jessica J Rathore Geetanjali G Beck-Woedl Stefanie S Haack Tobias B TB Pavlidou Despoina C DC Atallah Isis I Vodopiutz Julia J Janecke Andreas R AR Hsieh Tzung-Chien TC Lesmann Hellen H Klinkhammer Hannah H Krawitz Peter M PM Lemke Johannes R JR Jamra Rami Abou RA Nieto Marta M Tümer Zeynep Z Platzer Konrad K

European journal of human genetics : EJHG 20230830 11

Heterozygous, pathogenic CUX1 variants are associated with global developmental delay or intellectual disability. This study delineates the clinical presentation in an extended cohort and investigates the molecular mechanism underlying the disorder in a Cux1<sup>+/-</sup> mouse model. Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished individuals). We analyze brain CUX1 expression and susceptibility to epilepsy in Cux1<su ...[more]

PMID: 37644171

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Dataset Information

CUX1-related neurodevelopmental disorder: deep insights into phenotype-genotype spectrum and underlying pathology.

Publications

CUX1-related neurodevelopmental disorder: deep insights into phenotype-genotype spectrum and underlying pathology.

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