SETBP1 variants outside the degron disrupt DNA-binding, transcription and neuronal differentiation capacity to cause a heterogeneous neurodevelopmental disorder
Year: 2025
Type: article
Study design: Observational Study
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.
Source: Nature Communications
Authors: Maggie M. K. Wong, Rosalie A. Kampen, Ruth O. Braden, Gökberk Alagöz, Michael S. Hildebrand, Alexander J. M. Dingemans, Jean Corbally, Joery den Hoed, Ezequiel Mendoza, Willemijn J. J. Claassen, Christopher Barnett, Meghan Barnett, Alfredo Brusco, Diana Carli, Bert B. A. de Vries, Frances Elmslie, Giovanni Battista Ferrero, Nadieh A. Jansen, Ingrid M. B. H. van de Laar, Alice Moroni, David Mowat, Lucinda Murray, Francesca Novara, Angela Peron, Ingrid E. Scheffer, Fabio Sirchia, Samantha J. Turner, Aglaia Vignoli, Arianna Vino, Sacha Weber, Wendy K. Chung, Marion Gerard, Vanesa López-González, Elizabeth Palmer, Angela T. Morgan, Bregje W. van Bon, Simon E. Fisher
Institutions: Max Planck Institute for Psycholinguistics, The University of Melbourne, Murdoch Children's Research Institute, Austin Health, Royal Children's Hospital, Radboud University Medical Center, Freie Universität Berlin, Women's and Children's Hospital, Azienda Ospedaliera Citta' della Salute e della Scienza di Torino, University of Turin, Ospedale Regina Margherita, St George's, University of London, Erasmus MC, UNSW Sydney, Sydney Children's Hospital, Sydney Children’s Hospitals Network, Royal North Shore Hospital, University of Milan, University of Utah, Ospedale San Paolo, Azienda Socio Sanitaria Territoriale Santi Paolo e Carlo, University of Pavia, Azienda Socio Sanitaria Territoriale Grande Ospedale Metropolitano Niguarda, Boston Children's Hospital, Harvard University, Instituto de Salud Carlos III, Instituto Murciano de Investigación Biosanitaria, Hospital Universitario Virgen de la Arrixaca, Radboud University Nijmegen, Donders Institute for Brain, Cognition and Behaviour
Language: English
Subfield: Genetics
Domain: Life Sciences
Open Access status: gold
Estimated APC paid: $6,990
Awards: Centre for Research Excellence in Speech and Language Neurobiology (CRE-SLANG), Precision Medicine in the Developmental and Epileptic Encephalopathies, G2379101456, Neurobiology of childhood speech and language disorders: advancing diagnosis, prognosis and management, G2611185475, Elucidating the neural pathways and genetic basis of speech, Genetics of epilepsy, Building and commercialising a digital speech tool (ADAAPT), Genetics of epilepsies and speech disorders, G8203088156, Biology of speech disorders: advancing diagnosis, prognosis & management, Neurobiology of childhood speech disorders: improving detection, diagnosis and clinical care
OpenAlex ID: W4415026956