General Report

Clinical characteristics and genetic analysis of SETBP1 haploinsufficiency disorder

  • Ruiping WAN ,
  • Xiaofei HUANG ,
  • Xingguang YE ,
  • Yanling WU ,
  • Jiemin DAI ,
  • Zhigang LIU
Expand
  • Department of Pediatrics, Foshan Women and Children Hospital Affiliated to Southern Medical University, Foshan 528000, Guangdong, China

Received date: 2022-08-29

  Online published: 2023-06-12

Abstract

Objective To summarize the clinical phenotype and genetic variation characteristics of patients with SETBP1 haploinsufficiency disorder (SETBP1-HD). Methods The genetic variations and clinical characteristics of three children with SETBP1-HD from January 2019 to December 2021 were retrospectively analyzed. Results Three SETBP1-HD children, 1 boy and 2 girls (identical twins), were 5 years old and 5 months old respectively. All patients presented moderate intellectual disabilities, motor and language developmental retardation. Compared with the verbal expression ability, the language comprehension ability of case 1 was better, and the child also had attention deficits. Case 2 and case 3 had febrile seizures. No obvious autism-like manifestations were observed in the 3 cases, and no specific manifestations were observed on head MRI scan and video electroencephalogram. De novo heterozygous variations in SETBP1 gene were found in all patients, including a frameshift variation (c.607delG/p.Gly203Valfs*4) from case 1 and a nonsense variation (c.1873C>T/p.Arg625*) from case 2 and case 3. Conclusions SETBP1-HD is a different phenotype from Schinzel-Giedion syndrome. The main clinical features of SETBP1-HD are intellectual disabilities, speech and language disorder, and motor developmental retardation. Speech and language disorders are the core symptoms of the disease. Some patients may have behavioral problems and convulsive seizures. Loss of function variation in SETBP1 resulting in haploinsufficiency is the cause of this disease. Patients can benefit partially from supportive treatment such as rehabilitation training, behavioral therapy, and anticonvulsant medication. Prenatal diagnosis is an important measure to prevent this disease.

Cite this article

Ruiping WAN , Xiaofei HUANG , Xingguang YE , Yanling WU , Jiemin DAI , Zhigang LIU . Clinical characteristics and genetic analysis of SETBP1 haploinsufficiency disorder[J]. Journal of Clinical Pediatrics, 2023 , 41(6) : 450 -454 . DOI: 10.12372/jcp.2023.22e1155

References

[1] Bellini E, Luoni M, Cancellieri C, et al. SETBP1 accumulation induces P53 inhibition and genotoxic stress in neural progenitors underlying neurodegeneration in Schinzel-Giedion syndrome[J]. Nat Commun, 2021, 12(1): 4050.
[2] Antonyan L, Ernst C. Putative roles of SETBP1 dosage on the set oncogene to affect brain development[J]. Front Neurosci, 2022, 16: 813430.
[3] Jansen NA, Braden RO, Srivastava S, et al. Clinical delineation of SETBP1 haploinsufficiency disorder[J]. Eur J Hum Genet, 2021, 29(8): 1198-1205.
[4] 路通, 王艺. 幼儿特殊面容伴发育落后与多系统畸形[J]. 中国当代儿科杂志, 2017, 19(8): 921-925.
[5] Richards S, Aziz N, Bale S, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology[J]. Genet Med, 2015, 17(5): 405-424.
[6] Coe BP, Witherspoon K, Rosenfeld JA, et al. Refining analyses of copy number variation identifies specific genes associated with developmental delay[J]. Nat Genet, 2014, 46(10): 1063-1071.
[7] Morgan A, Braden R, Wong MMK, et al. Speech and language deficits are central to SETBP1 haploinsufficiency disorder[J]. Eur J Hum Genet, 2021, 29(8): 1216-1225.
[8] Filges I, Shimojima K, Okamoto N, et al. Reduced expression by SETBP1 haploinsufficiency causes developmental and expressive language delay indicating a phenotype distinct from Schinzel-Giedion syndrome[J]. J Med Genet, 2011, 48(2): 117-122.
[9] Rauch A, Wieczorek D, Graf E, et al. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: an exome sequencing study[J]. Lancet, 2012, 380(9854): 1674-1682.
[10] Hamdan FF, Srour M, Capo-Chichi JM, et al. De novo mutations in moderate or severe intellectual disability[J]. PLoS Genet, 2014, 10(10): e1004772.
[11] Liu WL, He ZX, Li F, et al. Schinzel-Giedion syndrome: a novel case, review and revised diagnostic criteria[J]. J Genet, 2018, 97(1): 35-46.
[12] Eising E, Carrion-Castillo A, Vino A, et al. A set of regulatory genes co-expressed in embryonic human brain is implicated in disrupted speech development[J]. Mol Psychiatry, 2019, 24(7): 1065-1078.
[13] Leonardi E, Bettella E, Pelizza MF, et al. Identification of SETBP1 mutations by gene panel sequencing in individuals with intellectual disability or with "developmental and epileptic encephalopathy"[J]. Front Neurol, 2020, 11: 593446.
[14] Hildebrand MS, Jackson VE, Scerri TS, et al. Severe childhood speech disorder: gene discovery highlights transcriptional dysregulation[J]. Neurology, 2020, 94(20): e2148-e2167.
[15] Hu C, Liu D, Luo T, et al. Phenotypic spectrum and long-term outcome of children with genetic early-infantile-onset developmental and epileptic encephalopathy[J]. Epileptic Disord, 2022, 24(2): 343-352.
[16] Liu L, Feng X, Liu S, et al. Whole-genome sequencing combined RNA-sequencing analysis of patients with mutations in SET binding protein 1[J]. Front Neurosci, 2022, 16: 980000.
Outlines

/