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Review
. 2024 May 6;24(1):309.
doi: 10.1186/s12887-024-04779-y.

Novel SETBP1 D874V adjacent to the degron causes canonical schinzel-giedion syndrome: a case report and review of the literature

Jing Zheng  1   2 , Meiqun Gu  1   2 , Shasha Xiao  1   2 , Chongzhen Li  1   2 , Hongying Mi  1   2 , Xiaoyan Xu  3   4
Affiliations
Review

Novel SETBP1 D874V adjacent to the degron causes canonical schinzel-giedion syndrome: a case report and review of the literature

Jing Zheng et al. BMC Pediatr. .

Abstract

Schinzel-Giedion syndrome (SGS) is a severe multisystem disorder characterized by distinctive facial features, profound intellectual disability, refractory epilepsy, cortical visual impairment, hearing loss, and various congenital anomalies. SGS is attributed to gain-of-function (GoF) variants in the SETBP1 gene, with reported variants causing canonical SGS located within a 12 bp hotspot region encoding SETBP1 residues aa868-871 (degron). Here, we describe a case of typical SGS caused by a novel heterozygous missense variant, D874V, adjacent to the degron. The female patient was diagnosed in the neonatal period and presented with characteristic facial phenotype (midface retraction, prominent forehead, and low-set ears), bilateral symmetrical talipes equinovarus, overlapping toes, and severe bilateral hydronephrosis accompanied by congenital heart disease, consistent with canonical SGS. This is the first report of a typical SGS caused by a, SETBP1 non-degron missense variant. This case expands the genetic spectrum of SGS and provides new insights into genotype-phenotype correlations.

Keywords: SETBP1; Hydronephrosis; Neonate; Schinzel-Giedion syndrome.

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Conflict of interest statement

The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Phenotypic variants of the patient. (A) Characteristic midface retraction, frontal bossing, and low-set ears at 1 day after birth; (B) A grossly distended abdomen
Fig. 2
Fig. 2
Photographs show the clinical features of the patient in this study. (A) Chest radiographs at 1 day after birth show wide ribsn (B, C) Color doppler ultrasonography at 10 days after birth shows widened bodies and anterior horns of lateral ventricles; (D, E) Color doppler ultrasonography at 10 days after birth shows severe hydronephrosis was found in both kidneys, bilateral pelvis and calyces were severely dilated with a “palette” appearancete (F) Abdominal CT at 1 day after birth shows Significant increase in the size of both kidneys, signs of severe hydronephrosis in both kidneys
Fig. 3
Fig. 3
Sanger sequencing confirms de novo c.2621 A > T variant(p.Asp874Val) in the SETBP1 gene in the patient
Fig. 4
Fig. 4
In-silico analysis of SETBP1 c.2621 A > T/p.Asp874Val variant. (A) Protein-DNA/RNA docking using HDOCK server (http://hdock.phys.hust.edu.cn/) (hybrid algorithm of template-based modeling and ab initio free docking). As shown in Fig. 4A: Green represents SETBP1 protein and sky blue represents E3 ubiquitin ligase. S876, D868, S869, G870, I871, G872, T873 and D874 of SETBP1 form interactions with L48, K50, G101, C103, R105, P158 and N159 of E3 ubiquitin ligase, which in turn promote SETBP1 binding to E3 ubiquitin ligase and thus ubiquitination occurs. The hotspot variants D868, S869, G870 and I871 of SETBP1 gene significantly affect the binding of SETBP1 to E3 ubiquitin ligase, thereby affecting ubiquitination. The D874V variant reported in this paper is also in the vicinity of the SETBP1 gene binding E3 ubiquitin ligase, which may also affect the binding of SETBP1 protein to E3 ubiquitin ligase and thus affect SETBP1 protein ubiquitination, ultimately leading to the development of the disease. (B) Alignment of the SETBP1 sequences revealed that the amino acid residues at position 874 were strictly conserved
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