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Learn more about Schinzel-Giedion Syndrome and the important role that SETBP1 gain of function mutations play in neurodevelopment and oncology.

In this photo: Ophelia

About The Schinzel-Giedion Syndrome Foundation

The Schinzel-Giedion Syndrome Foundation was started in November 2019 by the parent of a child with Schinzel-Giedion Syndrome (SGS) living in UK and is a UK registered charity. The Board of Trustees are an international group of SGS parents and the members of the Scientific and Medical Advisory Board (SMAB) span the globe and consist of basic researchers at renowned institutions, medical geneticists and paediatric clinicians, and industry-level therapeutic developers.

About Schinzel-Giedion Syndrome

SGS is an ultra-rare developmental disorder arising from de novo germline mutations in the SETBP1 gene (SET-Binding Protein 1) located on chromosome 18. Seven known mutations alter a 12-basepair-long region encoding a protein degradation initiation site (“degron”). As a consequence, functional SETBP1 protein exists for longer than intended. Because SETBP1 appears to act as an epigenetic regulatory protein, turning on and/or off target genes, and as a protein-protein interaction with SET, the result of persistent SETBP1 levels is developmental dysregulation across several organ systems. Patients manifest facial dysmorphism, severe global developmental delay, and seizure (often medically refractory) as prominent features. Gastrointestinal, urinary, and respiratory tract problems are also common. “Classical SGS” patients have an average lifespan of 18-48 months. “Atypical SGS” patients have slightly modified phenotypes and may have a lifespan extending beyond the average. 1

SETBP1 in Epilepsy

The team at The Schinzel-Giedion Syndrome Foundation is taking a mission-driven approach to improve the quality of life for children with SGS. In consultation with SGS parents and clinicians, we are targeting refractory seizure and proactively identifying research groups willing to accelerate this mission.

Existing work has elucidated SETBP1 mechanistic pathology and suggests targets whose modulation may impact the seizure burden for children with Schinzel-Giedion Syndrome. Given that SETBP1 acts transiently during embryonic development, we must look to intervene at the post-natal stage. As well as targeting SETBP1,  we are evaluating targets “downstream” of SETBP1 where dysregulation/dysfunction appears to manifest post-natally as paediatric refractory seizure.

Given the very low incidence of Schinzel-Giedion Syndrome (approximately 100 cases globally), we will also be examining which SGS-relevant targets are implicated in other rare neurodevelopmental diseases manifesting seizure.


SETBP1 in Oncology

SGS-identical SETBP1 mutations are found somatically in a number of myeloid malignancies. These mutations often confer a more aggressive cancer and worse prognosis for the patient. The mechanism here appears to be two-fold:

(1) stabilization of the SET protein via SETBP1-SET binding and resulting complex formation with PP2A (SETBP1-SET-PP2A) to inhibit innate PP2A tumour suppressor function ; and

(2) dysregulation of SETBP1-mediated gene expression via aberrant SETBP1 DNA binding and epigenetic complex activity.

Further, SET overexpression and consequential PP2A inhibition appear in a number of solid tumour indications (e.g. colon, pancreatic). This suggests PP2A reactivation could deliver meaningful clinical outcomes for SET-overexpressing and/or SET/PP2A-inhibited cancer populations.

Relevant References:

      1. Acuna-Hidalgo R, Deriziotis P, Steehouwer M, et al. Overlapping SETBP1 gain-of-function mutations in Schinzel-Giedion Syndrome and hematologic malignancies. PLOS Genetics 13(3) e1006683
      2. Trimarchi T, Ntziachristos P, Aifantis I. A new player in SETs in myeloid malignancy. Nature Genetics 2013:45, 846-847
      3. Winkelmann N, Schafer V, Rinke J, et al. Only SETBP1 hotspot mutations are associated with refractory disease in myeloid malignancies. J Cancer Res Clin Oncol. 2017 Dec;143(12):2511-2519
      4. Laborde RR, Patnaik MM, Lasho TL, et al. SETBP1 mutations in 415 patients with primary myelofibrosis or chronic myelomonocytic leukemia: independent prognostic in CMML. Leukemia 2013;27(10): 2100-2102
      5. Cristobal I, Blanco FJ, Garcia-Orti L, et al. SETBP1 overexpression is a novel leukemogenic mechanism that predicts adverse outcome in elderly patients with acute myeloid leukemia. Blood 2010;115(3): 615-625
      6. Piazza R, Magistroni V, Redaelli S, et al. SETBP1 induces transcription of a network of development genes by acting as an epigenetic hub. Nat Comm 2018;9: 2192
      7. Allen-Petersen B, Risom T, Feng Z, et al. Activation of PP2A and inhibition of mTOR synergistically reduce MYC signaling and decrease tumor growth in pancreatic ductal adenocarcinoma. Cancer Res. 2019; 79(1): 209–219
      8. Hoischen A, van Bon B, Gilissen et al. De novo mutations of SETBP1 cause Schinzel-Giedion syndrome. Nature Genetics 2010;42(6): 483-485
      9. Banfi, F., Rubio, A., Zaghi, M. et al. SETBP1 accumulation induces P53 inhibition and genotoxic stress in neural progenitors underlying neurodegeneration in Schinzel-Giedion syndrome. Nat Commun 12, 4050 (2021).
      10. Zaghi M, Banfi F, Massimino L, et al. Balanced SET levels favor the correct enhancer

        repertoire during cell fate acquisition. Nat Commun. 2023. Jun 3;14(1):3212.

      11. Kohyanagi N, Ohama T. The impact of SETBP1 mutations in neurological diseases and

        cancer. Genes Cells. 2023. Sep;28(9):629-641.

      12. Whitlock JH, Wilk EJ, Howton TC, et al. The landscape of SETBP1 gene expression and

        transcription factor activity across human tissues. bioRxiv [Preprint]. 2023 Oct


      13. Whitlock JH, Soelter TM, Howton TC, et al. Cell-type-specific gene expression and

        regulation in the cerebral cortex and kidney of atypical Setbp1S858R Schinzel Giedion

        Syndrome mice. J Cell Mol Med. 2023 Nov;27(22):3565-3577.

      14. Whitlock JH, Wilk EJ, Howton TC, et al. The landscape of SETBP1 gene expression and

        transcription factor activity across human tissues. PLoS One. 2024 Jan 2;19(1):e0296328

      15. Antonyan L, Ernst C. Putative Roles of SETBP1 Dosage on the SET Oncogene to Affect

        Brain Development. Front Neurosci. 2022 May 24;16:813430.

If you would like to find out more about Schinzel-Giedion Syndrome and ongoing SETBP1 research, please contact Matthew Burkhardt, Chair of our Scientific and Medical Advisory Board.

Want to learn more about Schinzel-Giedion Syndrome?

Read the new GeneReviews for Schinzel-Giedion Syndrome written by experts Dr Jessica Duis and Dr Bregje van Bon who are both on our Scientific and Medical Advisory Board.

GeneReviews is an international point-of-care resource for busy clinicians. It provides clinically relevant and medically actionable information for inherited conditions in a standardized journal-style format, covering diagnosis, management, and genetic counseling for patients and their families. Each chapter in GeneReviews is written by one or more experts on the specific condition or disease and goes through a rigorous editing and peer review process before being published online.
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