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Clinical and functional study of two de novo variations of CDKL5 gene

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Abstract

The cyclin-dependent kinase like 5 (CDKL5) gene variation is X-linked dominant and is associated with type 2 developmental and epileptic encephalopathy (DEE). Although numerous cases of CDKL5 have been reported, there is limited discussion regarding functional verification. We described two children with DEE caused by de novo variations of CDKL5 gene, analyzed their clinical manifestations, and performed genetic testing on their gene variation sites. The two cases presented with tonic seizures followed by epileptic spasms, indicative of refractory epilepsy. Physical examination revealed abnormal facial features, including wide eye distance, low nose base, and high nose bridge. Both cases exhibited developmental disabilities. Cranial magnetic resonance imaging (MRI) showed widening of the bilateral frontotemporal extracerebral space. Genetic testing identified variations at the gene sites c.463 + 4A > G (splicing) and c.1854_1861delCAAAGTGA (p.D618Efs*18). Minigene experiments further confirmed that the intronic variation c.463 + 4A > G (splicing) disrupted splicing, leading to protein truncation. CDKL5 gene variation can lead to DEE, and intron variation site c.463 + 4A > G (splicing) can cause protein truncation, which is a pathogenic variation.

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References

  1. Bahi-Buisson N, Bienvenu T (2012) CDKL5-related disorders: from clinical description to molecular genetics. Mol Syndromol 2(3–5):137–152. https://doi.org/10.1159/000331333

    Article  CAS  PubMed  Google Scholar 

  2. Báez-Mendoza R, Schultz W (2013) The role of the striatum in social behavior. Front Neurosci 7:233. https://doi.org/10.3389/fnins.2013.00233

    Article  PubMed  PubMed Central  Google Scholar 

  3. Zhu YC, Xiong ZQ (2019) Molecular and synaptic bases of CDKL5 disorder. Dev Neurobiol 79(1):8–19. https://doi.org/10.1002/dneu.22639

    Article  PubMed  Google Scholar 

  4. Katayama S, Sueyoshi N, Inazu T, Kameshita I (2020) Cyclin-dependent kinase-like 5 (CDKL5): possible cellular signalling targets and involvement in CDKL5 deficiency disorder. Neural Plast 2020:6970190. https://doi.org/10.1155/2020/6970190

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Piacentini C, Menghini P, Setti M (1988) An external aprismatic layer on temporary and permanent teeth. Bulletin du Groupement Int pour la Recherche Scientifique en Stomatologie & Odontologie 31(3–4):177–187

    CAS  Google Scholar 

  6. Wang HT, Zhu ZA, Li YY, Lou SS, Yang G, Feng X et al (2021) CDKL5 deficiency in forebrain glutamatergic neurons results in recurrent spontaneous seizures. Epilepsia 62(2):517–528. https://doi.org/10.1111/epi.16805

    Article  CAS  PubMed  Google Scholar 

  7. Demarest ST, Olson HE, Moss A, Pestana-Knight E, Zhang X, Parikh S et al (2019) CDKL5 deficiency disorder: relationship between genotype, epilepsy, cortical visual impairment, and development. Epilepsia 60(8):1733–1742. https://doi.org/10.1111/epi.16285

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J et al (2015) 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. Genet Med 17(5):405–424. https://doi.org/10.1038/gim.2015.30

    Article  PubMed  PubMed Central  Google Scholar 

  9. Rosas-Vargas H, Bahi-Buisson N, Philippe C, Nectoux J, Girard B, N’Guyen Morel MA et al (2008) Impairment of CDKL5 nuclear localisation as a cause for severe infantile encephalopathy. J Med Genet 45(3):172–178. https://doi.org/10.1136/jmg.2007.053504

    Article  CAS  PubMed  Google Scholar 

  10. Bahi-Buisson N, Kaminska A, Boddaert N, Rio M, Afenjar A, Gérard M et al (2008) The three stages of epilepsy in patients with CDKL5 mutations. Epilepsia 49(6):1027–1037. https://doi.org/10.1111/j.1528-1167.2007.01520.x

    Article  CAS  PubMed  Google Scholar 

  11. Mirzaa GM, Paciorkowski AR, Marsh ED, Berry-Kravis EM, Medne L, Alkhateeb A et al (2013) CDKL5 and ARX mutations in males with early-onset epilepsy. Pediatr Neurol 48(5):367–377. https://doi.org/10.1016/j.pediatrneurol.2012.12.030

    Article  PubMed  PubMed Central  Google Scholar 

  12. Lilles S, Talvik I, Noormets K, Vaher U, Õunap K, Reimand T et al (2016) CDKL5 gene-related epileptic encephalopathy in Estonia: four cases, one novel mutation causing severe phenotype in a boy, and overview of the literature. Neuropediatrics 47(6):361–367. https://doi.org/10.1055/s-0036-1586730

    Article  CAS  PubMed  Google Scholar 

  13. Siri B, Varesio C, Freri E, Darra F, Gana S, Mei D et al (2021) CDKL5 deficiency disorder in males: five new variants and review of the literature. Eur J Paediatric Neurol 33:9–20. https://doi.org/10.1016/j.ejpn.2021.04.007

    Article  CAS  Google Scholar 

  14. Zhao Y, Zhang X, Bao X, Zhang Q, Zhang J, Cao G et al (2014) Clinical features and gene mutational spectrum of CDKL5-related diseases in a cohort of Chinese patients. BMC Med Genet 15:24. https://doi.org/10.1186/1471-2350-15-24

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Authors and Affiliations

  1. Department of Imaging, The Fourth Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, China

    Yang You

  2. Department of Pediatrics, The Second Hospital of Hebei Medical University, Shijiazhuang, 050000, Hebei, China

    Xinyi Men & Xiuxia Wang

  3. Department of Neurology, Hebei Children’s Hospital, Hebei Children’s Hospital Affiliated to Hebei Medical University, 133 Jianhua Nan Street, Shijiazhuang, 050031, Hebei, China

    Wenjuan Wu, Shan Liu, Suzhen Sun & Baoguang Li

  4. Department of Rehabilitation, Shijiazhuang Hospital of Traditional Chinese Medicine, 233 Zhongshan Road, Shijiazhuang, Hebei, 050000, China

    Xuexin He

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Contributions

BG L carried out the studies, participated in collecting data, and drafted the manuscript. ZZ Q participated in the acquisition, analysis, and interpretation of data and drafted the manuscript. WP W participated in project guidance. All authors read and approved the final manuscript.

Corresponding authors

Correspondence to Xiuxia Wang or Baoguang Li.

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Ethics approval and consent to participate

All procedures were performed in accordance with the ethical standards laid down in the 1964 Declaration of Helsinki and its later amendments. This study was approved by Ethics Committee of Hebei Children’s Hospital and Institutional Review Board of Hebei Children’s Hospital (approval number 2021[152]). Participants have consented to the submission of the case report.

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The participants have consented to the submission of the case report.

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The authors declare no competing interests.

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You, Y., Men, X., Wu, W. et al. Clinical and functional study of two de novo variations of CDKL5 gene. Neurogenetics 24, 263–271 (2023). https://doi.org/10.1007/s10048-023-00731-x

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  • DOI: https://doi.org/10.1007/s10048-023-00731-x

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