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

Autor: Haviland I; Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, USA.; Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA., Hector RD; Simons Initiative for the Developing Brain & Patrick Wild Centre, Centre for Discovery Brain Sciences, University of Edinburgh, Edinburgh, UK., Swanson LC; Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, USA.; Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA., Verran AS; Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital, Boston, Massachusetts, USA., Sherrill E; Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital, Boston, Massachusetts, USA., Frazier Z; Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, USA.; Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA., Denny AM; Division of Pediatric Neurology, University of Saskatchewan, Saskatoon, Saskatchewan, Canada., Lucash J; Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, USA.; Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA., Zhang B; Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, USA., Dubbs HA; Division of Child Neurology, Children's Hospital of Philadelphia, Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA., Marsh ED; Division of Child Neurology, Children's Hospital of Philadelphia, Department of Neurology, University of Pennsylvania Perelman School of Medicine, Philadelphia, Pennsylvania, USA., Weisenberg JL; Department of Pediatric Neurology, Washington University School of Medicine, St. Louis, Missouri, USA., Leonard H; Telethon Kids Institute, The University of Western Australia, Perth, Western Australia, Australia., Crippa M; Research Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy., Cogliati F; Research Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy., Russo S; Research Laboratory of Medical Cytogenetics and Molecular Genetics, IRCCS Istituto Auxologico Italiano, Milan, Italy., Suter B; Division of Child Neurology, Texas Children's Hospital, Departments of Neurology and Pediatrics, Baylor College of Medicine, Houston, Texas, USA., Rajaraman R; Division of Pediatric Neurology, UCLA Mattel Children's Hospital, Los Angeles, California, USA., Percy AK; Department of Pediatrics, University of Alabama at Birmingham, Birmingham, Alabama, USA., Schreiber JM; Division of Epilepsy, Neurophysiology, and Critical Care Neurology, Children's National Hospital, Washington, DC, USA., Demarest S; Department of Pediatrics and Neurology, Precision Medicine Institute, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, Colorado, USA., Benke TA; Department of Pediatrics, Pharmacology and Neurology, University of Colorado School of Medicine and Children's Hospital Colorado, Aurora, Colorado, USA., Chopra M; Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, USA.; Rosamund Stone Zander Translational Neuroscience Center, Boston Children's Hospital, Harvard Medical School, Boston, Massachusetts, USA., Yu TW; Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, USA.; Division of Genetics and Genomics, Department of Pediatrics, Boston Children's Hospital, Boston, Massachusetts, USA., Olson HE; Department of Neurology, Boston Children's Hospital, Boston, Massachusetts, USA.; Division of Epilepsy and Clinical Neurophysiology, Boston Children's Hospital, Boston, Massachusetts, USA.
Jazyk: angličtina
Zdroj: American journal of medical genetics. Part A [Am J Med Genet A] 2025 Jan; Vol. 197 (1), pp. e63843. Date of Electronic Publication: 2024 Aug 28.
DOI: 10.1002/ajmg.a.63843
Abstrakt: 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.
(© 2024 Wiley Periodicals LLC.)
Databáze: MEDLINE
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