Journal Article

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

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

2025

Overview

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. Different types of SETBP1 variants cause variable developmental syndromes with only partial clinical and functional overlaps. Here, the authors report that SETBP1 variants outside the degron region impair DNA-binding, transcription, and neuronal differentiation capacity and morphologies.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13 / 13/1 / 13/106 / 13/109 / 14/19 / 14/63 / 38/88 / 38/91 / 631/208/366 / 692/4017 / 692/699/375/366 / 82/80 / Adolescent / Amino acids / Binding / Carrier Proteins - genetics / Carrier Proteins - metabolism / Cell Differentiation - genetics / Cell growth / Child / Child, Preschool / Congenital diseases / Degrons / Deoxyribonucleic acid / Diagnosis / Differentiation / Disorders / DNA / DNA damage / DNA-Binding Proteins - genetics / DNA-Binding Proteins - metabolism / Female / Genes / Genomes / Genotype & phenotype / Genotypes / Haploinsufficiency / Heterogeneity / Humanities and Social Sciences / Humans / Intellectual Disability - genetics / Male / Morphology / multidisciplinary / Mutation, Missense / Neurodevelopment / Neurodevelopmental disorders / Neurodevelopmental Disorders - genetics / Neurodevelopmental Disorders - metabolism / Neurodevelopmental Disorders - pathology / Neurogenesis / Neurons - metabolism / Nuclear Proteins - genetics / Nuclear Proteins - metabolism / Patients / Phenotypes / Phenotyping / Proteins / Science / Science (multidisciplinary) / Transcription / Transcription, Genetic / Transcriptomics / Ubiquitination