title: Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion syndrome and hematologic malignancies.
abstract: Schinzel-Giedion syndrome (SGS) is a rare developmental disorder characterized by multiple malformations, severe neurological alterations and increased risk of malignancy. SGS is caused by de novo germline mutations clustering to a 12bp hotspot in exon 4 of SETBP1. Mutations in this hotspot disrupt a degron, a signal for the regulation of protein degradation, and lead to the accumulation of SETBP1 protein. Overlapping SETBP1 hotspot mutations have been observed recurrently as somatic events in leukemia. We collected clinical information of 47 SGS patients (including 26 novel cases) with germline SETBP1 mutations and of four individuals with a milder phenotype caused by de novo germline mutations adjacent to the SETBP1 hotspot. Different mutations within and around the SETBP1 hotspot have varying effects on SETBP1 stability and protein levels in vitro and in in silico modeling. Substitutions in SETBP1 residue I871 result in a weak increase in protein levels and mutations affecting this residue are significantly more frequent in SGS than in leukemia. On the other hand, substitutions in residue D868 lead to the largest increase in protein levels. Individuals with germline mutations affecting D868 have enhanced cell proliferation in vitro and higher incidence of cancer compared to patients with other germline SETBP1 mutations. Our findings substantiate that, despite their overlap, somatic SETBP1 mutations driving malignancy are more disruptive to the degron than germline SETBP1 mutations causing SGS. Additionally, this suggests that the functional threshold for the development of cancer driven by the disruption of the SETBP1 degron is higher than for the alteration in prenatal development in SGS. Drawing on previous studies of somatic SETBP1 mutations in leukemia, our results reveal a genotype-phenotype correlation in germline SETBP1 mutations spanning a molecular, cellular and clinical phenotype.
authors.affiliation: Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Rocio
authors.identifier: 0000-0001-9413-0348
authors.initials: R
authors.lastname: Acuna-Hidalgo
authors.affiliation: Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.
authors.forename: Pelagia
authors.initials: P
authors.lastname: Deriziotis
authors.affiliation: Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Marloes
authors.initials: M
authors.lastname: Steehouwer
authors.affiliation: Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Christian
authors.initials: C
authors.lastname: Gilissen
authors.affiliation: Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.
authors.forename: Sarah A
authors.initials: SA
authors.lastname: Graham
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.
authors.forename: Sipko
authors.identifier: 0000-0001-9204-0197
authors.initials: S
authors.lastname: van Dam
authors.affiliation: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Julie
authors.initials: J
authors.lastname: Hoover-Fong
authors.affiliation: GeneDx, Gaithersburg, Maryland, United States of America.
authors.forename: Aida B
authors.initials: AB
authors.lastname: Telegrafi
authors.affiliation: Institute of Pathology and Genetics (IPG), Gosselies, Belgium.
authors.forename: Anne
authors.initials: A
authors.lastname: Destree
authors.affiliation: Department of Pediatrics and Rare Disorders, Medical University, Wroclaw, Poland.
authors.forename: Robert
authors.initials: R
authors.lastname: Smigiel
authors.affiliation: Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Lindsday A
authors.initials: LA
authors.lastname: Lambie
authors.affiliation: Medical Genetics Department, Koç University School of Medicine (KUSOM), İstanbul, Turkey.
authors.forename: Hülya
authors.initials: H
authors.lastname: Kayserili
authors.affiliation: Medical Genetics Department, İstanbul Medical Faculty, İstanbul University, İstanbul, Turkey.
authors.forename: Umut
authors.initials: U
authors.lastname: Altunoglu
authors.affiliation: Medical Genetics Unit, Anna Meyer Children's University Hospital, Florence, Italy.
authors.forename: Elisabetta
authors.initials: E
authors.lastname: Lapi
authors.affiliation: University of Florence, Genetic Science, Firenze, Italy.
authors.forename: Maria Luisa
authors.initials: ML
authors.lastname: Uzielli
authors.affiliation: División de Pediatría, Pontificia Universidad Católica de Chile and Unidad de Genética, Hospital Dr. Luis Calvo Mackenna, Santiago Chile.
authors.forename: Mariana
authors.initials: M
authors.lastname: Aracena
authors.affiliation: Department of Pediatric Genetics, Akdeniz University Medical School, Antalya, Turkey.
authors.forename: Banu G
authors.initials: BG
authors.lastname: Nur
authors.affiliation: Department of Pediatric Genetics, Akdeniz University Medical School, Antalya, Turkey.
authors.forename: Ercan
authors.initials: E
authors.lastname: Mihci
authors.affiliation: Laboratory of Human Genetics, Biology Institute, Federal University of Bahia (UFBA), Bahia, Brazil.
authors.forename: Lilia M A
authors.initials: LM
authors.lastname: Moreira
authors.affiliation: Hospital Santa Izabel, Salvador-Bahia, Brazil.
authors.forename: Viviane
authors.initials: V
authors.lastname: Borges Ferreira
authors.affiliation: CERES-Genetica Reference Center and Studies in Medical Genetics and Instituto Fernandes Figueira / Fiocruz, Rio de Janeiro, Brazil.
authors.forename: Dafne D G
authors.initials: DD
authors.lastname: Horovitz
authors.affiliation: Center for Human Genome Studies, Institute of Biosciences, USP, Sao Paulo, Brazil.
authors.forename: Katia M
authors.initials: KM
authors.lastname: da Rocha
authors.affiliation: Department of Medical Genetics, Children's Memorial Health Institute, Warsaw, Poland.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Jezela-Stanek
authors.affiliation: Department of Clinical Genetics, Sophia Children's Hospital, Erasmus MC, Rotterdam, The Netherlands.
authors.forename: Alice S
authors.initials: AS
authors.lastname: Brooks
authors.affiliation: Institute of Human Genetics, University of Bonn, Bonn, Germany and Department of Neonatology and Pediatric Intensive Care, Children's Hospital, University of Bonn, Bonn, Germany.
authors.forename: Heiko
authors.initials: H
authors.lastname: Reutter
authors.affiliation: Division of Neurogenetics, Kennedy Krieger Institute, Departments of Neurology and Pediatrics, The Johns Hopkins Hospital, Baltimore, Maryland, United States of America.
authors.forename: Julie S
authors.initials: JS
authors.lastname: Cohen
authors.affiliation: Division of Neurogenetics, Kennedy Krieger Institute, Departments of Neurology and Pediatrics, The Johns Hopkins Hospital, Baltimore, Maryland, United States of America.
authors.forename: Ali
authors.initials: A
authors.lastname: Fatemi
authors.affiliation: Abteilung Neuropädiatrie, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Germany.
authors.forename: Martin
authors.initials: M
authors.lastname: Smitka
authors.affiliation: Division of Genetics & Metabolism, Phoenix Children's Hospital, Phoenix, Arizona, United States of America.
authors.forename: Theresa A
authors.initials: TA
authors.lastname: Grebe
authors.affiliation: Institute for Clinical Genetics, TU Dresden, Dresden, Germany.
authors.forename: Nataliya
authors.initials: N
authors.lastname: Di Donato
authors.affiliation: Department of Genetics, Guy's and St. Thomas' NHS Foundation Trust, London, United Kingdom.
authors.forename: Charu
authors.initials: C
authors.lastname: Deshpande
authors.affiliation: North West Thames Regional Genetics Unit, Kennedy Galton Centre, North West London Hospitals NHS Trust, Northwick Park & St Marks Hospital, Harrow, Middlesex, United Kingdom.
authors.forename: Anthony
authors.initials: A
authors.lastname: Vandersteen
authors.affiliation: Neurogenetics Unit, Department of Medical Genetics School of Medicine of Ribeirao Preto, University of Sao Paulo, Sao Paulo, Brazil.
authors.forename: Charles
authors.initials: C
authors.lastname: Marques Lourenço
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
authors.forename: Andreas
authors.initials: A
authors.lastname: Dufke
authors.affiliation: Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
authors.forename: Eva
authors.initials: E
authors.lastname: Rossier
authors.affiliation: Unité de foetopathologie, Hôpital Pellegrin, Place Amélie Raba Léon, Bordeaux, France.
authors.forename: Gwenaelle
authors.initials: G
authors.lastname: Andre
authors.affiliation: Institute of Medical Genetics, University of Zurich, Schlieren, Switzerland.
authors.forename: Alessandra
authors.initials: A
authors.lastname: Baumer
authors.affiliation: Division of Human Genetics, National Health Laboratory Service and School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa.
authors.forename: Careni
authors.initials: C
authors.lastname: Spencer
authors.affiliation: Genetic Health Queensland, Royal Brisbane and Women's Hospital, Brisbane, Queensland and School of Medicine, The University of Queensland, Brisbane, Queensland, Australia.
authors.forename: Julie
authors.initials: J
authors.lastname: McGaughran
authors.affiliation: University of Groningen, University Medical Center Groningen, Department of Genetics, Groningen, the Netherlands.
authors.forename: Lude
authors.initials: L
authors.lastname: Franke
authors.affiliation: Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.|Institute of Genetic Medicine, International Centre for Life, Newcastle University, Newcastle upon Tyne, United Kingdom.
authors.forename: Joris A
authors.initials: JA
authors.lastname: Veltman
authors.affiliation: Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Bert B A
authors.initials: BB
authors.lastname: De Vries
authors.affiliation: Institute of Medical Genetics, University of Zurich, Schlieren, Switzerland.
authors.forename: Albert
authors.initials: A
authors.lastname: Schinzel
authors.affiliation: Language and Genetics Department, Max Planck Institute for Psycholinguistics, Nijmegen, The Netherlands.|Donders Institute for Brain, Cognition and Behaviour, Radboud University, Nijmegen, The Netherlands.
authors.forename: Simon E
authors.initials: SE
authors.lastname: Fisher
authors.affiliation: Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Human Genetics, Donders Centre for Neuroscience, Radboud University Medical Center, Nijmegen, The Netherlands.|Department of Internal Medicine and Radboud Center for Infectious Diseases (RCI), Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Alexander
authors.initials: A
authors.lastname: Hoischen
authors.affiliation: Department of Human Genetics, Radboud Institute of Molecular Life Sciences, Radboud University Medical Center, Nijmegen, The Netherlands.
authors.forename: Bregje W
authors.identifier: 0000-0003-2234-0105
authors.initials: BW
authors.lastname: van Bon
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D015153:Blotting, Western; D002352:Carrier Proteins / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D049109:Cell Proliferation / Q000235:genetics; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D019465:Craniofacial Abnormalities / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D018095:Germ-Line Mutation; D057809:HEK293 Cells; D006228:Hand Deformities, Congenital / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D019337:Hematologic Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008607:Intellectual Disability / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009154:Mutation; D009264:Nails, Malformed / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics* / Q000378:metabolism; D010641:Phenotype
chemical_list: D002352:Carrier Proteins; D009687:Nuclear Proteins; C425066:SETBP1 protein, human