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

Henry Oppermann, Elia Marcos-Grañeda, Linnea A. Weiss, Christina A. Gurnett, Anne Marie Jelsig, Susanne H. Vineke, Bertrand Isidor, Sandra Mercier, Kari Magnussen, Pia Zacher, Mona Hashim, Alistair T. Pagnamenta, Simone Race, Siddharth Srivastava, Zoë Frazier, Robert Maiwald, Matthias Pergande, Donatella Milani, Martina Rinelli, Jonathan LevyIlona Krey, Paolo Fontana, Fortunato Lonardo, Stephanie Riley, Jasmine Kretzer, Julia Rankin, Linda M. Reis, Elena V. Semina, Miriam S. Reuter, Stephen W. Scherer, Maria Iascone, Denisa Weis, Christina R. Fagerberg, Charlotte Brasch-Andersen, Lars Kjaersgaard Hansen, Alma Kuechler, Nathan Noble, Alice Gardham, Jessica Tenney, Geetanjali Rathore, Stefanie Beck-Woedl, Tobias B. Haack, Despoina C. Pavlidou, Isis Atallah, Julia Vodopiutz, Andreas R. Janecke, Tzung Chien Hsieh, Hellen Lesmann, Hannah Klinkhammer, Peter M. Krawitz, Johannes R. Lemke, Rami Abou Jamra, Marta Nieto, Zeynep Tümer, Konrad Platzer

Research output: Contribution to journalArticlepeer-review

3 Scopus citations


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 Through international collaboration, we assembled the phenotypic and molecular information for 34 individuals (23 unpublished individuals).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.

Original languageEnglish
Pages (from-to)1251-1260
Number of pages10
JournalEuropean Journal of Human Genetics
Issue number11
StatePublished - Nov 2023


Dive into the research topics of 'CUX1-related neurodevelopmental disorder: deep insights into phenotype-genotype spectrum and underlying pathology'. Together they form a unique fingerprint.

Cite this