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

Maggie M. K. Wong (), Rosalie A. Kampen, Ruth O. Braden, Gökberk Alagöz, Michael S. Hildebrand, Alexander J. M. Dingemans, Jean Corbally, Joery Hoed, Ezequiel Mendoza, Willemijn J. J. Claassen, Christopher Barnett, Meghan Barnett, Alfredo Brusco, Diana Carli, Bert B. A. Vries, Frances Elmslie, Giovanni Battista Ferrero, Nadieh A. Jansen, Ingrid M. B. H. 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. Bon and Simon E. Fisher ()
Additional contact information
Maggie M. K. Wong: Max Planck Institute for Psycholinguistics
Rosalie A. Kampen: Max Planck Institute for Psycholinguistics
Ruth O. Braden: University of Melbourne Austin Health Victoria
Gökberk Alagöz: Max Planck Institute for Psycholinguistics
Michael S. Hildebrand: University of Melbourne Austin Health Victoria
Alexander J. M. Dingemans: Radboud University Medical Center
Jean Corbally: Max Planck Institute for Psycholinguistics
Joery Hoed: Max Planck Institute for Psycholinguistics
Ezequiel Mendoza: Freie Universität Berlin
Willemijn J. J. Claassen: Max Planck Institute for Psycholinguistics
Christopher Barnett: Women’s and Children’s Hospital
Meghan Barnett: Women’s and Children’s Hospital
Alfredo Brusco: University of Torino
Diana Carli: University of Torino
Bert B. A. Vries: Radboud University Medical Center
Frances Elmslie: University of London
Giovanni Battista Ferrero: University of Torino
Nadieh A. Jansen: Radboud University Medical Center
Ingrid M. B. H. Laar: University Medical Center Rotterdam
Alice Moroni: University of Torino
David Mowat: Sydney Children’s Hospitals Network Randwick
Lucinda Murray: St Leonards
Francesca Novara: Microgenomics srl
Angela Peron: San Paolo Hospital
Ingrid E. Scheffer: University of Melbourne Austin Health Victoria
Fabio Sirchia: University of Pavia
Samantha J. Turner: University of Melbourne Austin Health Victoria
Aglaia Vignoli: Università degli Studi di Milano
Arianna Vino: Max Planck Institute for Psycholinguistics
Sacha Weber: Reference center for Rare Diseases and Developmental Anomalies
Wendy K. Chung: Boston Children’s Hospital Boston
Marion Gerard: Reference center for Rare Diseases and Developmental Anomalies
Vanesa López-González: CIBERER-ISCIII
Elizabeth Palmer: UNSW
Angela T. Morgan: Murdoch Children’s Research Institute
Bregje W. Bon: Radboud University Medical Center
Simon E. Fisher: Max Planck Institute for Psycholinguistics

Nature Communications, 2025, vol. 16, issue 1, 1-23

Abstract: 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.

Date: 2025
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DOI: 10.1038/s41467-025-64074-x

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