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A novel heterozygous ZBTB18 missense mutation in a family with non-syndromic intellectual disability

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Abstract

Intellectual disability (ID) is a common neurodevelopmental disorder characterized by significantly impaired adaptive behavior and cognitive capacity. High throughput sequencing approaches have revealed the genetic etiologies for 25–50% of ID patients, while inherited genetic mutations were detected in <5% cases. Here, we investigated the genetic cause for non-syndromic ID in a Han Chinese family. Whole genome sequencing was performed on identical twin sisters diagnosed with ID, their respective children, and their asymptomatic parents. Data was filtered for rare variants, and in silico prediction tools were used to establish pathogenic alleles. Candidate mutations were validated by Sanger sequencing. In silico modeling was used to evaluate the mutation’s effects on the protein encoded by a candidate coding gene. A novel heterozygous variant in the ZBTB18 gene c.1323C>G (p.His441Gln) was identified. This variant co-segregated with affected individuals in an autosomal dominant pattern and was not detected in asymptomatic family members. Molecular studies reveal that a p.His441Gln substitution disrupts zinc binding within the second zinc finger and disrupts the capacity for ZBTB18 to bind DNA. This is the first report of an inherited ZBTB18 mutation for ID. This study further validates WGS for the accurate molecular diagnosis of ID.

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Data availability

The data and images used in this article are available from the corresponding author on reasonable request.

Abbreviations

ID:

intellectual disability

CNVs:

copy number variants

NGS:

next-generation sequencing

WES:

whole-exome sequencing

WGS:

whole-genome sequencing

MR:

magnetic resonance

MRI:

magnetic resonance imaging

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Acknowledgements

We are very grateful to the family members for their participation in this study.

Funding

This study was supported by the National Key Research and Development Program of China (2022YFC2703700, 2022YFC2703702) and the Program for Changjiang Scholars and Innovative Research Team in University (ID: IRT0935).

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Author notes

  1. Nana Li and Hong Kang contributed equally to this work.

Authors and Affiliations

  1. National Center for Birth Defect Monitoring, West China Second University Hospital, Sichuan University, Chengdu, Sichuan, China

    Nana Li, Hong Kang, Zhen Liu, Ying Deng, Meixian Wang, Lu Li, Yanping Wang, Jun Zhu & Ping Yu

  2. Key Laboratory of Birth Defects and Related Diseases of Women and Children, Sichuan University, Ministry of Education, Chengdu, Sichuan, China

    Nana Li, Hong Kang, Zhen Liu, Ying Deng, Meixian Wang, Lu Li, Yanping Wang, Jun Zhu & Ping Yu

  3. Department of Gynaecology and Obstetrics, Changyi Maternal and Child Care Hospital, Weifang, Shandong, China

    Yanna Zou

  4. Department of Gynaecology and Obstetrics, Wuhou District People’s Hospital, Chengdu, Sichuan, China

    Hong Qin

  5. Department of Obstetrics and Gynecology, Pidu District People’s Hospital, Chengdu, China

    Xiaoqiong Qiu

  6. Faculty of Health Sciences, Curtin University, Bentley, Australia

    Mark Agostino & Julian I-T Heng

  7. Curtin Institute for Computation, Curtin University, Bentley, Australia

    Mark Agostino

  8. Curtin Medical School, Curtin University, Bentley, Australia

    Mark Agostino

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  1. Nana Li
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  2. Hong Kang
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Contributions

Nana Li and Ping Yu developed the study design. Nana Li, Hong Kang, Julian Heng, and Ping Yu conducted the experiment and drafted the manuscript. Zhen Liu, Ying Deng, Meixian Wang, and Lu Li assisted in analyzing the genomic data. Yanna Zou, Hong Qin, and Xiaoqiong Qiu participated in the clinical evaluation of the patients. Mark Agostino and Julian I-T Heng performed molecular modeling studies. Yanping Wang, Jun Zhu, and Julian I-T Heng participated in the critical review and revision of the manuscript. All authors have read and approved the final manuscript.

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Correspondence to Julian I-T Heng or Ping Yu.

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Li, N., Kang, H., Zou, Y. et al. A novel heterozygous ZBTB18 missense mutation in a family with non-syndromic intellectual disability. Neurogenetics 24, 251–262 (2023). https://doi.org/10.1007/s10048-023-00727-7

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