Mapping Variants in CDKL5 to Assess Potential Impact of DNA or Rna-based Therapies
Abstract number :
3.121
Submission category :
12. Genetics / 12A. Human Studies
Year :
2024
Submission ID :
548
Source :
www.aesnet.org
Presentation date :
12/9/2024 12:00:00 AM
Published date :
Authors :
Presenting Author: Hailey Osika, BA – Boston Children's Hospital
Aubrie Soucy Verran, BA – Boston Children's Hospital
Lindsay Swanson, MS, CGC – Boston Children's Hospital
Zoë Frazier, MS, CGC – Boston Children's Hospital
Isabel Haviland, MD – Boston Children's Hospital
Jenna Lucash, BA – Boston Children's Hospital
Nancy Aly, MD – Boston Children's Hospital
Christelle Moufawad el Achkar, MD – Boston Children's Hospital
William Hong, MD – Boston Children's Hospital
Helen Leonard, MBChB – Telethon Kids Institute
Jenny Downs, PhD – Telethon Kids Institute
Holly Dubs, MS, CGC – Children's Hospital of Philadelphia
Timothy Yu, MD, PhD – Boston Children's Hospital
Bernhard Suter, MD – Baylor College of Medicine
Rajsekar Rajaraman, MD, MS – UCLA Mattel Children's Hospital
Judith Weisenberg, MD – Washington University of St. Louis
Elia Pestana Knight, MD – Cleveland Clinic Epilepsy Center
Eric Marsh, MD PhD – Children's Hospital of Philadelphia
Dana Price, MD – NYU Langone Health
Scott Demarest, MD – Children's Hospital Colorado
Tim Benke, MD – University of Colorado School of Medicine
Heather Olson, MD, MS – Boston Children's Hospital, Harvard Medical School
Rationale: CDKL5 deficiency disorder (CDD) is an X-linked developmental and epileptic encephalopathy. Clinical features include early onset epilepsy, developmental and motor delay, sleep disturbances, hypotonia, and cerebral visual impairment. Currently, there is no known targeted gene therapy for CDD. We analyzed the range of variants associated with CDD, including assessment of their relationship to key functional domains such as the highly conserved catalytic domain. The goal was to define recurrent variants and/or regions of high variant density that may be targeted by DNA or RNA-based therapies (e.g. anti-sense oligonucleotides and gene-editing).
Methods: We performed a retrospective analysis of 214 individuals with a diagnosis of CDD enrolled in the International CDKL5 Clinical Research Network (ICCRN) or the CDKL5 Clinic study at Boston Children’s Hospital. We analyzed CDKL5 variants obtained by physicians and researchers associated with the aforementioned protocols and institutions.
Results: We report 214 CDKL5 (NM_001323289.2) variants within the exons of hCDKL5_1, the dominant brain isoform, identified in individuals with a diagnosis of CDD. We described 71 missense variants in the catalytic domain (33.2%), 95 truncating variants (44.4%, 44 frameshift, 50 nonsense), 33 partial or whole gene deletions (15.4%), and 15 intronic splice variants (7.0%). One previously reported recurrent missense variant p.V718M that results in exon 14 skipping is categorized as truncating/frameshift. Missense variants were distributed across exons 2-11 but enriched in exons 6 and 8. Outside of the catalytic domain, exon 12 (the largest exon), harbored the largest number of truncating variants (n=37). Of the 37 variants in exon 12, 22 were nonsense and 15 were frameshift. Missense and truncating variants are mapped in Figure 1.
Conclusions: Here we present an analysis of CDKL5 variants to inform efficient DNA and RNA-targeted therapeutic strategies. We identify variant hotspot regions both within and outside of the catalytic domain including exons 6, 8, and 12. In particular, deleterious variants in exon 12 were most prevalent (17.5% of reported variants). The future therapeutic strategies that target these exons could impact a maximum number of individuals with CDD.
Future initiatives aim to incorporate CDKL5 variants identified by other CDKL5 Centers of Excellence, the International CDKL5 Disorder Database and diagnostic laboratories. The increased variant sample size would help identify regions that may be ideal therapeutic targets. Our work serves to define the genetic spectrum of CDD and support the development of disease-modifying therapies.
Funding: National Institute of Neurological Diseases and Stroke (5K23NS107646-05, 3K23NS107646-05S1, U01NS114312), International Foundation for CDKL5 Research
Genetics