Novel <i>SETBP1</i> mutation in a chinese family with intellectual disability

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Abstract

Background

Intellectual disability (ID) is characterized by an IQ < 70, which implies below-average intellectual function and a lack of skills necessary for daily living. ID may occur due to multiple causes, such as metabolic, infectious, and chromosomal causes. ID affects approximately 1–3% of the population; however, the cause can be identified in only 25% of clinical patients.

Methods

To find the cause of genetic ID in a family, we performed whole-exome sequencing and Sanger sequencing to confirm the presence of a SETBP1 variant and real-time quantitative polymerase chain reaction to detect SETBP1 expression in the proband and normal controls.

Results

A novel variant, c.942_943insGT (p. Asp316TrpfsTer28), was found in SETBP1. Furthermore, we observed that SETBP1 expression in patients was only 20% that of normal controls (P < 0.05).

Conclusion

A heterozygous variant in SETBP1 associated with ID was found. This report provides further evidence for its genetic basis and support for clinical genetic diagnosis.

Supplementary Information

The online version contains supplementary material available at 10.1186/s12920-023-01649-x.

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Most cited references 9

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Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies.

David T Miller, Margaret P Adam, Swaroop Aradhya … (2010)

Chromosomal microarray (CMA) is increasingly utilized for genetic testing of individuals with unexplained developmental delay/intellectual disability (DD/ID), autism spectrum disorders (ASD), or multiple congenital anomalies (MCA). Performing CMA and G-banded karyotyping on every patient substantially increases the total cost of genetic testing. The International Standard Cytogenomic Array (ISCA) Consortium held two international workshops and conducted a literature review of 33 studies, including 21,698 patients tested by CMA. We provide an evidence-based summary of clinical cytogenetic testing comparing CMA to G-banded karyotyping with respect to technical advantages and limitations, diagnostic yield for various types of chromosomal aberrations, and issues that affect test interpretation. CMA offers a much higher diagnostic yield (15%-20%) for genetic testing of individuals with unexplained DD/ID, ASD, or MCA than a G-banded karyotype ( approximately 3%, excluding Down syndrome and other recognizable chromosomal syndromes), primarily because of its higher sensitivity for submicroscopic deletions and duplications. Truly balanced rearrangements and low-level mosaicism are generally not detectable by arrays, but these are relatively infrequent causes of abnormal phenotypes in this population (<1%). Available evidence strongly supports the use of CMA in place of G-banded karyotyping as the first-tier cytogenetic diagnostic test for patients with DD/ID, ASD, or MCA. G-banded karyotype analysis should be reserved for patients with obvious chromosomal syndromes (e.g., Down syndrome), a family history of chromosomal rearrangement, or a history of multiple miscarriages. Copyright (c) 2010 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.

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Refining analyses of copy number variation identifies specific genes associated with developmental delay

Bradley P. Coe, Kali Witherspoon, Jill Rosenfeld … (2014)

Copy number variants (CNVs) are associated with many neurocognitive disorders; however, these events are typically large and the underlying causative gene is unclear. We created an expanded CNV morbidity map from 29,085 children with developmental delay versus 19,584 healthy controls, identifying 70 significant CNVs. We resequenced 26 candidate genes in 4,716 additional cases with developmental delay or autism and 2,193 controls. An integrated analysis of CNV and single-nucleotide variant (SNV) data pinpointed ten genes enriched for putative loss of function. Patient follow-up on a subset identified new clinical subtypes of pediatric disease and the genes responsible for disease-associated CNVs. This includes haploinsufficiency of SETBP1 associated with intellectual disability and loss of expressive language and truncations of ZMYND11 in patients with autism, aggression and complex neuropsychiatric features. This combined CNV and SNV approach facilitates the rapid discovery of new syndromes and neuropsychiatric disease genes despite extensive genetic heterogeneity.

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PP2A impaired activity is a common event in acute myeloid leukemia and its activation by forskolin has a potent anti-leukemic effect.

M Calasanz, I Cristóbal, M Alonso … (2011)

Protein phosphatase 2A (PP2A) is a human tumor suppressor that inhibits cellular transformation by regulating the activity of several signaling proteins critical for malignant cell behavior. PP2A has been described as a potential therapeutic target in chronic myeloid leukemia, Philadelphia chromosome-positive acute lymphoblastic leukemia and B-cell chronic lymphocytic leukemia. Here, we show that PP2A inactivation is a recurrent event in acute myeloid leukemia (AML), and that restoration of PP2A phosphatase activity by treatment with forskolin in AML cells blocks proliferation, induces caspase-dependent apoptosis and affects AKT and ERK1/2 activity. Moreover, treatment with forskolin had an additive effect with Idarubicin and Ara-c, drugs used in standard induction therapy in AML patients. Analysis at protein level of the PP2A activation status in a series of patients with AML at diagnosis showed PP2A hyperphosphorylation in 78% of cases (29/37). In addition, we found that either deregulated expression of the endogenous PP2A inhibitors SET or CIP2A, overexpression of SETBP1, or downregulation of some PP2A subunits, might be contributing to PP2A inhibition in AML. In conclusion, our results show that PP2A inhibition is a common event in AML cells and that PP2A activators, such as forskolin or FTY720, could represent potential novel therapeutic targets in AML.

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Author and article information

Contributors

Hong-Mei Xiao: hmxiao@csu.edu.cn

Journal

Journal ID (nlm-ta): BMC Med Genomics

Journal ID (iso-abbrev): BMC Med Genomics

Title: BMC Medical Genomics

Publisher: BioMed Central (London )

ISSN (Electronic): 1755-8794

Publication date (Electronic): 5 October 2023

Publication date PMC-release: 5 October 2023

Publication date Collection: 2023

Volume: 16

Electronic Location Identifier: 233

Affiliations

[1 ]School of Basic Medical Science, Hunan University of Medicine, ( https://ror.org/05htk5m33) Huaihua, Hunan China

[2 ]Center for System Biology, Data Sciences, and Reproductive Health, School of Basic Medical Science, Central South University, ( https://ror.org/00f1zfq44) Changsha, Hunan China

Article

Publisher ID: 1649

DOI: 10.1186/s12920-023-01649-x

PMC ID: 10552191

PubMed ID: 37798664

SO-VID: bb73b845-8628-4fba-9b9e-33d4d0037fb3

License:

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 statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data.

History

Date received : 1 March 2023

Date accepted : 28 August 2023

Funding

Funded by: National Key R&D Program of China

Award ID: 2017YFC1001100

Funded by: Construction Project of the Center of Reproductive Health, Central South University

Award ID: 164990007

Custom metadata

ScienceOpen disciplines: Genetics

Keywords: setbp1,intellectual disability,autosomal dominant mental retardation 29,whole-genome sequencing

Data availability:

ScienceOpen disciplines: Genetics

Keywords: setbp1, intellectual disability, autosomal dominant mental retardation 29, whole-genome sequencing

Novel SETBP1 mutation in a chinese family with intellectual disability

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Abstract

Background

Methods

Results

Conclusion

Supplementary Information

Related collections

Arabidopsis genomics

Most cited references 9

Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies.

Refining analyses of copy number variation identifies specific genes associated with developmental delay

PP2A impaired activity is a common event in acute myeloid leukemia and its activation by forskolin has a potent anti-leukemic effect.

Author and article information

Contributors

Journal

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Article

History

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