SETBP1 variants outside the degron disrupt DNA-binding, transcription and neuronal differentiation capacity to cause a heterogeneous neurodevelopmental disorder

Different types of germline de novo SETBP1 variants cause clinically distinct and heterogeneous neurodevelopmental disorders: Schinzel-Giedion syndrome (SGS, via missense variants at a critical degron region) and SETBP1-haploinsufficiency disorder. However, due to the lack of systematic investigation of genotype-phenotype associations of different types of SETBP1 variants, and limited understanding of its roles in neurodevelopment, the extent of clinical heterogeneity and how this relates to underlying pathophysiological mechanisms remains elusive. This imposes challenges for diagnosis. Here, we present a comprehensive investigation of the largest cohort to date of individuals carrying SETBP1 missense variants outside the degron region (n = 18). We performed thorough clinical and speech phenotyping with functional follow-up using cellular assays and transcriptomics. Our findings suggest that such variants cause a clinically and functionally variable developmental syndrome, showing only partial overlaps with classical SGS and SETBP1-haploinsufficiency disorder. We provide evidence of loss-of-function pathophysiological mechanisms impairing ubiquitination, DNA-binding, transcription, and neuronal differentiation capacity and morphologies. In contrast to SGS and SETBP1 haploinsufficiency, these effects are independent of protein abundance. Overall, our study provides important novel insights into diagnosis, patient care, and aetiology of SETBP1-related disorders.

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Publication Details

Journal
Nature Communications
Published
2025-10-10
DOI
https://doi.org/10.1038/s41467-025-64074-x
Citations
2
Primary Topic
Genetics and Neurodevelopmental Disorders
Type
article
Field-Weighted Citation Impact
3.63

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article

SETBP1 variants outside the degron disrupt DNA-binding, transcription and neuronal differentiation capacity to cause a heterogeneous neurodevelopmental disorder

Bregje W.M. van Bon, Gökberk Alagöz, Sacha Weber, Giovanni Battista Ferrero et al.
2 citations
Nature Communications
Genetics and Neurodevelopmental Disorders
3.63
article

SETBP1 variants outside the degron disrupt DNA-binding, transcription and neuronal differentiation capacity to cause a heterogeneous neurodevelopmental disorder

Bregje W.M. van Bon, Gökberk Alagöz, Sacha Weber, Giovanni Battista Ferrero, Alice Moroni, Arianna Vino, Ruth Braden, Ezequiel Mendoza, Samantha J. Turner, Joery den Hoed, Wendy K. Chung, Francesca Novara, Meghan Barnett, Lucinda Murray, Aglaia Vignoli, David Mowat, Ingrid Eileen Scheffer, Michael S. Hildebrand, Angela Peron, Christopher Barnett, Frances Elmslie, Fabio Sirchia, Rosalie A. Kampen, Elizabeth E. Palmer, Alexander J.M. Dingemans, Alfredo Brusco, Angela Tamsin Morgan, Diana Carli, Bert B.A. de Vries, Nadieh A. Jansen, Ingrid M.B.H. van de Laar, Simon E. Fisher, Vanesa López‐González, Willemijn Claassen, Marion Gérard, Maggie M. K. Wong, Jean Corbally
article en
2 citations

Abstract

Different types of germline de novo SETBP1 variants cause clinically distinct and heterogeneous neurodevelopmental disorders: Schinzel-Giedion syndrome (SGS, via missense variants at a critical degron region) and SETBP1-haploinsufficiency disorder. However, due to the lack of systematic investigation of genotype-phenotype associations of different types of SETBP1 variants, and limited understanding of its roles in neurodevelopment, the extent of clinical heterogeneity and how this relates to underlying pathophysiological mechanisms remains elusive. This imposes challenges for diagnosis. Here, we present a comprehensive investigation of the largest cohort to date of individuals carrying SETBP1 missense variants outside the degron region (n = 18). We performed thorough clinical and speech phenotyping with functional follow-up using cellular assays and transcriptomics. Our findings suggest that such variants cause a clinically and functionally variable developmental syndrome, showing only partial overlaps with classical SGS and SETBP1-haploinsufficiency disorder. We provide evidence of loss-of-function pathophysiological mechanisms impairing ubiquitination, DNA-binding, transcription, and neuronal differentiation capacity and morphologies. In contrast to SGS and SETBP1 haploinsufficiency, these effects are independent of protein abundance. Overall, our study provides important novel insights into diagnosis, patient care, and aetiology of SETBP1-related disorders.

Nature CommunicationsVol. 16(1)
Boston Children's Hospital (US), AOL (United States) (US), Royal Children's Hospital (AU), Harvard University (US), Radboud University Nijmegen (NL), The University of Melbourne (AU), St George's, University of London (GB), University of Milan (IT), University of Utah (US), University of Pavia (IT), Royal North Shore Hospital (AU), Women's and Children's Hospital (AU), Erasmus MC (NL), Radboud University Medical Center (NL), UNSW Sydney (AU), Azienda Ospedaliera Citta' della Salute e della Scienza di Torino (IT), Max Planck Institute for Psycholinguistics (NL), Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda (IT), Ospedale San Paolo (IT), Sydney Children's Hospital (AU), Torino e-district (IT), Ospedale Regina Margherita (IT), Murdoch Children's Research Institute (AU), Hospital Universitario Virgen de la Arrixaca (ES), Boston Children's Museum (US), Austin Health (AU), Azienda Socio Sanitaria Territoriale Santi Paolo e Carlo, University of Turin (IT), Freie Universität Berlin (DE)
March of Dimes Foundation, Simons Foundation Autism Research Initiative, European Commission, Radboud Universiteit, Max-Planck-Gesellschaft, Medical Research Council, National Health and Medical Research Council
Openalex Percentile: Top 6%
Genetics and Neurodevelopmental Disorders
3.63
DOIOpen Access PDFOpenAlex
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