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Alu-specific microhomology-mediated deletions in CDKL5 in females with early-onset seizure disorder

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Abstract

Mutations in the cyclin-dependent kinase-like 5 (CDKL5) gene in Xp22.13 have been associated with infantile spasms, early-onset intractable epilepsy, and a Rett syndrome (RTT)-like phenotype. Using array comparative genomic hybridization, we identified variable-sized microdeletions involving exons 1–4 of the CDKL5 gene in three females with early-onset seizures. Two of these deletions were flanked by Alu repetitive elements and may have resulted from either non-allelic homologous recombination or the microhomology-mediated Fork Stalling and Template Switching/Microhomology-Mediated Break-Induced Replication mechanism. Our findings demonstrate the first instance of genomic deletion as the molecular basis of CDKL5 deficiency in females and highlight the importance of exon targeted array-CGH analysis for this gene in females with drug-resistant early-onset seizures.

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Acknowledgments

We are indebted to the families who participated in this study. Contract grant sponsor: Doris Duke Clinical Scientist Development Award and the Gillson Longenbaugh Foundation (SRL), NUCDF foundation, and NIH/NIGMS T32 (AE); contract grant number (GM07526) (AE). RAL is a Senior Scientific Investigator of Research to Prevent Blindness, New York, New York. PS was supported in part by Grant R13-0005-04/2008 from the Polish Ministry of Science and Higher Education.

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Authors and Affiliations

  1. Department of Molecular & Human Genetics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA

    Ayelet Erez, Amina J. Patel, Xueqing Wang, Zhilian Xia, Samarth S. Bhatt, William Craigen, Sau Wai Cheung, Richard A. Lewis, Ping Fang & Seema R. Lalani

  2. Department of Ophthalmology, Baylor College of Medicine, Houston, TX, USA

    Richard A. Lewis

  3. Department of Medicine, Baylor College of Medicine, Houston, TX, USA

    Richard A. Lewis

  4. Department of Pediatrics, Baylor College of Medicine, Houston, TX, USA

    Richard A. Lewis

  5. Sensory Genetics and Neurodevelopment, Bloomington, MN, USA

    Sandra L. H. Davenport

  6. Department of Molecular & Human Genetics, Baylor College of Medicine, One Baylor Plaza, Rm R809, Houston, TX, 77030, USA

    Pawel Stankiewicz

Authors
  1. Ayelet Erez
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  2. Amina J. Patel
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  3. Xueqing Wang
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  7. Sau Wai Cheung
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  8. Richard A. Lewis
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  9. Ping Fang
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  10. Sandra L. H. Davenport
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  11. Pawel Stankiewicz
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  12. Seema R. Lalani
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Corresponding author

Correspondence to Pawel Stankiewicz.

Additional information

Ayelet Erez and Amina J. Patel contributed equally to this work.

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Erez, A., Patel, A.J., Wang, X. et al. Alu-specific microhomology-mediated deletions in CDKL5 in females with early-onset seizure disorder. Neurogenetics 10, 363–369 (2009). https://doi.org/10.1007/s10048-009-0195-z

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  • DOI: https://doi.org/10.1007/s10048-009-0195-z

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