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Clinical genomics expands the link between erroneous cell division, primary microcephaly and intellectual disability

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Abstract

Primary microcephaly is a rare neurogenic and genetically heterogeneous disorder characterized by significant brain size reduction that results in numerous neurodevelopmental disorders (NDD) problems, including mild to severe intellectual disability (ID), global developmental delay (GDD), seizures and other congenital malformations. This disorder can arise from a mutation in genes involved in various biological pathways, including those within the brain. We characterized a recessive neurological disorder observed in nine young adults from five independent consanguineous Pakistani families. The disorder is characterized by microcephaly, ID, developmental delay (DD), early-onset epilepsy, recurrent infection, hearing loss, growth retardation, skeletal and limb defects. Through exome sequencing, we identified novel homozygous variants in five genes that were previously associated with brain diseases, namely CENPJ (NM_018451.5: c.1856A > G; p.Lys619Arg), STIL (NM_001048166.1: c.1235C > A; p.(Pro412Gln), CDK5RAP2 (NM_018249.6 c.3935 T > G; p.Leu1312Trp), RBBP8 (NM_203291.2 c.1843C > T; p.Gln615*) and CEP135 (NM_025009.5 c.1469A > G; p.Glu490Gly). These variants were validated by Sanger sequencing across all family members, and in silico structural analysis. Protein 3D homology modeling of wild-type and mutated proteins revealed substantial changes in the structure, suggesting a potential impact on function. Importantly, all identified genes play crucial roles in maintaining genomic integrity during cell division, with CENPJ, STIL, CDK5RAP2, and CEP135 being involved in centrosomal function. Collectively, our findings underscore the link between erroneous cell division, particularly centrosomal function, primary microcephaly and ID.

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Data availability

The data that support the finding of this study are available upon request from the corresponding author.

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Acknowledgements

We are thankful for the members of the family for their participation and help in the study. Amjad Khan is supported by the Humboldt Postdoctoral Research Fellowship Program Germany and Zhichao Miao is supported by the National Key R&D Programs of China (2023YFF1204700, 2023YFF1204701, 2021YFF1200900, 2021YFF1200903), the Natural Science Foundation of China (32270707), R&D Programs of Guangzhou Laboratory, (Grant No. SRPG22-003, SRPG22-006, SRPG22-007,GZNL2024A01002, GZNL2023A01006, HWYQ23-003, YW-YFYJ0102). The research by STA was supported by the King Abdullah University of Science and Technology (KAUST) through the baseline fund and the Award No. FCC/1/1976-33 and REI/1/4446-01 from the Office of Sponsored Research (OSR).

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Authors and Affiliations

  1. Department of Biotechnology, Abdul Wali Khan University, Mardan, 23200, Khyber Pakhtunkhwa, Pakistan

    Saima, Sajid Ali & Atif Kamil

  2. Department of Zoology, University of Lakki Marwat, Lakki, 28420, Khyber Pakhtunkhwa, Pakistan

    Amjad Khan

  3. Institute for Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany

    Amjad Khan

  4. Alexander Von Humboldt Fellowship Foundation, Berlin, Germany

    Amjad Khan

  5. School of Life Science and Technology, ShanghaiTech University, Shanghai, China

    Jiuhong Jiang

  6. Guangzhou National Laboratory, Guangzhou International Bio Island, Guangzhou, China

    Jiuhong Jiang

  7. GMU-GIBH Joint School of Life Sciences, The Guangdong-Hong Kong-Macau Joint Laboratory for Cell Fate Regulation and Diseases, Guangzhou National Laboratory, Guangzhou Medical University, Guangzhou, China

    Zhichao Miao

  8. Shanghai Key Laboratory of Anesthesiology and Brain Functional Modulation, Clinical Research Center for Anesthesiology and Perioperative Medicine Translational Research Institute of Brain and Brain-Like Intelligence, Shanghai Fourth People’s Hospital, School of Medicine, Tongji University, Shanghai, China

    Zhichao Miao

  9. Department of Zoology, Kohat University of Science & Technology, Kohat, 26000, Khyber Pakhtunkhwa, Pakistan

    Shahid Niaz Khan

  10. Department of Internal Medicine, Brody Medicine School, East Carolina University, Greenville, NC, USA

    Atif Kamil

  11. Biological and Environmental Science and Engineering Division, Computational Biology Research Center, King Abdullah University of Science and Technology (KAUST), Thuwal, 23955-6900, Kingdom of Saudi Arabia

    Stefan T. Arold

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Contributions

Conceptualization and Investigation: Siama, Amjad Khan, Sajid Ali. Data curation: Siama, Amjad Khan. Validation, methodology and formal analysis: Siama, Amjad Khan, Sajid Ali and Shahid Niaz Khan. Protein modeling: Jiuhong Jiang, Zhichao Miao and Stefan Arold. Supervision: Amjad Khan, Sajid Ali. Writing—original draft: Siama. Writing—reviewing and editing: all authors.

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Saima, Khan, A., Ali, S. et al. Clinical genomics expands the link between erroneous cell division, primary microcephaly and intellectual disability. Neurogenetics (2024). https://doi.org/10.1007/s10048-024-00759-7

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