Deletions in the CDKL5 5' untranslated region lead to CDKL5 deficiency disorder

Isabel Haviland^{1

2}, Ralph D Hector³, Lindsay C Swanson^{1

2}, Aubrie Soucy Verran⁴, Emma Sherrill⁴, Zoë Frazier^{1

2}, AnneMarie M Denny⁵, Jenna Lucash^{1

2}, Bo Zhang¹, Holly A Dubbs⁶, Eric D Marsh⁶, Judith L Weisenberg⁷, Helen Leonard⁸, Milena Crippa⁹, Francesca Cogliati⁹, Silvia Russo⁹, Bernhard Suter¹⁰, Rajsekar Rajaraman¹¹, Alan K Percy¹², John M Schreiber¹³, Scott Demarest¹⁴, Timothy A Benke¹⁵, Maya Chopra^{1

2}, Timothy W Yu^{1

4}, Heather E Olson^{1

16}

Affiliations

¹ Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, USA.
² Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
³ Simons Initiative for the Developing Brain & Patrick Wild Centre, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK.
⁴ Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital, Boston, Massachusetts, USA.
⁵ Division of Pediatric Neurology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
⁶ Division of Child Neurology, Children's Hospital of Philadelphia, Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
⁷ Department of Pediatric Neurology, Washington University School of Medicine, St. Louis, Missouri, USA.
⁸ Telethon Kids Institute, The University of Western Australia, Perth, Western Australia, Australia.
⁹ Research Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy.
¹⁰ Division of Child Neurology, Texas Children's Hospital, Departments of Neurology and Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
¹¹ Division of Pediatric Neurology, UCLA Mattel Children's Hospital, Los Angeles, California, USA.
¹² Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
¹³ Division of Epilepsy, Neurophysiology, and Critical Care Neurology, Children's National Hospital, Washington, DC, USA.
¹⁴ Department of Pediatrics and Neurology, Precision Medicine Institute, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, Colorado, USA.
¹⁵ Department of Pediatrics, Pharmacology and Neurology, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, Colorado, USA.
¹⁶ Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, Massachusetts, USA.

PMID: 39205479
PMCID: PMC11637933 (available on 2026-01-01)
DOI: 10.1002/ajmg.a.63843

Deletions in the CDKL5 5' untranslated region lead to CDKL5 deficiency disorder

Isabel Haviland et al. Am J Med Genet A. 2025 Jan.

. 2025 Jan;197(1):e63843.

doi: 10.1002/ajmg.a.63843. Epub 2024 Aug 28.

Authors

Affiliations

¹ Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, USA.
² Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA.
³ Simons Initiative for the Developing Brain & Patrick Wild Centre, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK.
⁴ Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital, Boston, Massachusetts, USA.
⁵ Division of Pediatric Neurology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada.
⁶ Division of Child Neurology, Children's Hospital of Philadelphia, Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA.
⁷ Department of Pediatric Neurology, Washington University School of Medicine, St. Louis, Missouri, USA.
⁸ Telethon Kids Institute, The University of Western Australia, Perth, Western Australia, Australia.
⁹ Research Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy.
¹⁰ Division of Child Neurology, Texas Children's Hospital, Departments of Neurology and Pediatrics, Baylor College of Medicine, Houston, Texas, USA.
¹¹ Division of Pediatric Neurology, UCLA Mattel Children's Hospital, Los Angeles, California, USA.
¹² Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA.
¹³ Division of Epilepsy, Neurophysiology, and Critical Care Neurology, Children's National Hospital, Washington, DC, USA.
¹⁴ Department of Pediatrics and Neurology, Precision Medicine Institute, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, Colorado, USA.
¹⁵ Department of Pediatrics, Pharmacology and Neurology, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, Colorado, USA.
¹⁶ Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, Massachusetts, USA.

PMID: 39205479
PMCID: PMC11637933 (available on 2026-01-01)
DOI: 10.1002/ajmg.a.63843

Abstract

Pathogenic variants in the cyclin-dependent kinase-like 5 (CDKL5) gene are associated with CDKL5 deficiency disorder (CDD), a severe X-linked developmental and epileptic encephalopathy. Deletions affecting the 5' untranslated region (UTR) of CDKL5, which involve the noncoding exon 1 and/or alternatively spliced first exons (exons 1a-e), are uncommonly reported. We describe genetic and phenotypic characteristics for 15 individuals with CDKL5 partial gene deletions affecting the 5' UTR. All individuals presented characteristic features of CDD, including medically refractory infantile-onset epilepsy, global developmental delay, and visual impairment. We performed RNA sequencing on fibroblast samples from three individuals with small deletions involving exons 1 and/or 1a/1b only. Results demonstrated reduced CDKL5 mRNA expression with no evidence of expression from alternatively spliced first exons. Our study broadens the genotypic spectrum for CDD by adding to existing evidence that deletions affecting the 5' UTR of the CDKL5 gene are associated with the disorder. We propose that smaller 5' UTR deletions may require additional molecular testing approaches such as RNA sequencing to determine pathogenicity.

Keywords: 5′ UTR; CDKL5; alternatively spliced exons; developmental and epileptic encephalopathy; exon 1; genotypic spectrum.

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Conflict of interest statement

Eric Marsh has received consulting fees from Acadia Pharmaceuticals, Stoke therapeutics, and Novartis regarding clinical trial design and patient management. He is a site PI for clinical trials from SK Life Pharmaceuticals, Epygenix Pharmaceuticals, Ionis Pharmaceuticals, Acadia Pharmaceuticals and Zogenix Pharmaceuticals. He has received research funds from International Rett syndrome foundation, International CDKL5 research foundation, Rett syndrome research trust, LouLou Foundation, Simons Foundation, Curaleaf Inc, and the NIH. Helen Leonard provided consultancy for Marinus, Acadia, Avexis and Orion; and clinical trials with Anavex and Newron. All consultancies are unrelated to this work, and all remuneration has been made to her department. Rajsekar Rajaraman is a consultant for Marinus Pharmaceuticals, Acadia Pharmaceuticals, Jazz Pharmaceuticals, and Nobel Pharmaceuticals. Alan K. Percy provides consulting for Acadia Pharmaceuticals and Neurogene. John M. Schreiber has received consulting fees from Neurocrine Inc, Denali Therapeutics, Xenon Pharmacueticals, has served on advisory boards for Stoke Therapeutics, Longboard Pharmacueticals, and Zogenix, and has served on speaker bureaus for Marinus Pharmacueticals, Zogenix, and UCB. He receives research funding paid to Children’s National Hospital from the NIH, the Mowat Wilson Syndrome Foundation, and The Dravet Syndrome Foundation, and is site principal investigator for clinical trials sponsored by Stoke Therapeutics, Eisa, Neurocrine, and Zogenix/ UCB. He also serves on medical/ scientific advisory boards for the Epilepsy Foundation, The Cute Syndrome Foundation, The Mowat Wilson Syndrome Foundation, The Bow Foundation, and Combined Brain.

Scott Demarest has consulted for Biomarin, Neurogene, Marinus, Tysha, Ultragenyx, Zogenix (UCB), Capsida, Encoded, Longboard, and Ovid Therapeutics. He has funding from the NIH, Project 8P and Mila’s Miracle Foundation. He also serves on advisory boards for the non-profit foundations Rare X, SLC6A1 Connect, Project 8P, Ring14 USA, FamilieSCN2A and N of 1 Collaborative. Timothy A. Benke has received research funding from GRIN2B Foundation, the International Foundation for CDKL5 Research, Loulou Foundation, the National Institutes of Health, and Simons Foundation; consultancy for Alcyone, AveXis, GRIN Therapeutics, FOXG1 Research Foundation, GW Pharmaceuticals, the International Rett Syndrome Foundation, Marinus Pharmaceuticals, Neurogene, Ovid Therapeutics Takeda Pharmaceutical Company Limited and Taysha; clinical trials with Acadia Pharmaceuticals Inc., GW Pharmaceuticals, Marinus Pharmaceuticals, Neurogene, Ovid Therapeutics and Rett Syndrome Research Trust; all remuneration has been made to his department. Timothy W. Yu has received consulting fees from Servier Pharmaceuticals, BioMarin, and SynaptixBio, and research grant support from the Ataxia Telangiectasia Children’s Project and EveryONE Medicines. He serves on the board of directors of the N=1 Collaborative and the Oligonucleotide Therapeutics Society, and a volunteer scientific advisor for several nonprofit rare disease foundations. Heather E. Olson has received consulting fees from Takeda Pharmaceuticals and Zogenix regarding clinical trial design, Ovid Therapeutics regarding clinical trial results, Marinus Pharmaceuticals regarding CDKL5 deficiency disorder, and has done consulting for the FOXG1 Research Foundation.

References

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Deletions in the CDKL5 5' untranslated region lead to CDKL5 deficiency disorder

Affiliations

Deletions in the CDKL5 5' untranslated region lead to CDKL5 deficiency disorder

Authors

Affiliations

Abstract

Conflict of interest statement

References

MeSH terms

Substances

Supplementary concepts

Grants and funding

LinkOut - more resources

Full Text Sources