SETBP1 variants outside the degron disrupt DNA-binding, transcription and neuronal differentiation capacity to cause a heterogeneous neurodevelopmental disorder
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.
Article Details
Authors (37)
Maggie M. K. Wong
Rosalie A. Kampen
Ruth O. Braden
Gökberk Alagöz
Michael S. Hildebrand
Department of Medicine (Austin Health), University of Melbourne
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
Department of Medicine (Austin Health), University of Melbourne
Fabio Sirchia
Samantha J. Turner
Aglaia Vignoli
Arianna Vino
Sacha Weber
Wendy K. Chung
Department of Pediatrics, Boston Children’s Hospital, Harvard Medical School
Marion Gerard
Vanesa López-González
Elizabeth Palmer
Angela T. Morgan
Bregje W. van Bon
Simon E. Fisher