Identification of a novel de novo mutation of SETBP1 and new findings of SETBP1 in tumorgenesis

Sep 24, 2026

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Background: Over the past decade, SETBP1 has been linked to distinct conditions depending on variant type or level, including Schinzel-Giedon syndrome, SETBP1 haploinsufficiency disorder (SETBP1-HD), and myeloid malignancies. Whole-exome sequencing was used to investigate a pregnant woman with mental retardation. Somatic SETBP1 variants in other cancers remain insufficiently studied, prompting this pancancer investigation of SETBP1. Results identified a novel heterozygous SETBP1 mutation (c.1724_1727del; p. D575Vfs*4) predicted to truncate the protein and associate reduced expression with SETBP1-HD. Pancancer analysis highlighted heightened attention for SETBP1 overexpression in bladder urothelial carcinoma (BLCA) and stomach adenocarcinoma (STAD). Conclusions: The de novo SETBP1 mutation explains the genetic cause of SETBP1-HD in the family, and BLCA/STAD may relate to SETBP1 overexpression.

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Abstract

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Wang et al. Orphanet Journal of Rare Diseases (2023) 18:107 [https://doi.org/10.1186/s13023-023-02705-6](https://doi.org/10.1186/s13023-023-02705-6) Orphanet Journal of Rare Diseases RESEARCH Open Access Identification of a novel de novo mutation of SETBP1 and new findings of SETBP1 in tumorgenesis Hongdan Wang1,2* , Yue Gao1, Litao Qin1, Mengting Zhang1, Weili Shi1, Zhanqi Feng3, Liangjie Guo1, Bofeng Zhu4* and Shixiu Liao 1* Abstract Background In the past decade, SETBP1 has attracted a lot of interest on that the same gene with different type or level (germline or somatic) of variants could provoke different pathologic consequences such as Schinzel-Giedon syndrome, SETBP1 Haploinsufficiency Disorder (SETBP1-HD) and myeloid malignancies. Whole exome sequencing was conducted to detect the etiology of a pregnant woman with mental retardation. As a new oncogene and potential marker of myeloid malignancies, somatic SETBP1 variants in other cancers were rarely studied. We performed a pancancer analysis of SETBP1 gene in different cancers for the first time. Results A novel heterozygous mutation of the SETBP1 gene (c.1724_ 1727del, p. D575Vfs*4) was found in the patient and the fetus and the mutation was predicted to result in a truncated protein. Reduced SETBP1 expression was associated with SETBP1-HD. The pan-cancer analysis of SETBP1 showed that SETBP1 overexpression should be given special attention in Bladder Urothelial Carcinoma (BLCA) and Stomach adenocarcinoma (STAD) . Conclusions The de novo SETBP1 mutation was the genetic cause of SETBP1-HD in the family. BLCA and STAD might be related to SETBP1 overexpression. Keywords SETBP1, SETBP1 haploinsufficiency disorder, Schinzel-Giedon syndrome, Tumorgenesis *Correspondence: Hongdan Wang [wanghongdan@zzu.edu.cn](wanghongdan@zzu.edu.cn)[ ](wanghongdan@zzu.edu.cn)Bofeng Zhu [zhubofeng7372@126.com](zhubofeng7372@126.com)[ ](zhubofeng7372@126.com)Shixiu Liao [ychslshx@zzu.edu.cn](ychslshx@zzu.edu.cn) 1 Medical Genetic Institute of Henan Province, Henan Provincial People’s Hospital, Zhengzhou University People’s Hospital, Zhengzhou, China 2 National Health Commission Key Laboratory of Birth Defects Prevention, Henan Key Laboratory of Population Defects Prevention, Zhengzhou, China 3 Department of Urology, The First People’s Hospital of Zhengzhou, Zhengzhou, China 4 Guangzhou Key Laboratory of Forensic Multi-Omics for Precision Identification, School of Forensic Medicine, Southern Medical University, Guangzhou, China Introduction SET-binding protein 1 (SETBP1, OMIM611060) localized in chromosome 18q21 and expressed predominantly in the nucleus [1]. This gene encoded a 170 kDa protein, and many transcriptional variants encoding different isoforms have been found (provided by RefSeq, Aug 2011). The known and predicted protein domains of SETBP1 contained a SKI homology region, a SET binding domain, three AT hooks and a repeat domain [2]. SETBP1 binded the SET nuclear oncogene which was involved in DNA replication by its SET binding domain [1]. Recent studies demonstrated the involvement of SETBP1 germline mutations in Schinzel-Giedion syndrome (SGS, OMIM269150) and SETBP1 Haploinsufficiency Disorder (SETBP1-HD, OMIM616078) and SETBP1 somatic mutations in several hematological malignancies [3–6]. © The Author(s) 2023. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by

FAQs

What genetic finding was identified in the patient and fetus?

A novel heterozygous de novo SETBP1 mutation (c.1724_1727del, p. D575Vfs*4) was identified and predicted to produce a truncated protein.

How does the mutation relate to SETBP1-HD?

Reduced SETBP1 expression was associated with SETBP1 haploinsufficiency disorder (SETBP1-HD), supporting a pathogenic role for the mutation.

Which cancers showed notable associations with SETBP1 overexpression?

Pancancer analysis indicated that SETBP1 overexpression should receive special attention in bladder urothelial carcinoma (BLCA) and stomach adenocarcinoma (STAD).

Sep 24, 2026

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