Journal article
De novo variants in CDKL1 and CDKL2 are associated with neurodevelopmental symptoms
American journal of human genetics, Vol.112(4), pp.846-862
04/2025
DOI: 10.1016/j.ajhg.2025.02.019
PMCID: PMC12081231
PMID: 40088891
Abstract
The CDKL (cyclin-dependent kinase-like) family consists of five members in humans, CDKL1-5, that encode serine-threonine kinases. The only member that has been associated with a Mendelian disorder is CDKL5, and variants in CDKL5 cause developmental and epileptic encephalopathy type 2 (DEE2). Here, we study four de novo variants in CDKL2 identified in five individuals, including three unrelated probands and monozygotic twins. These individuals present with overlapping symptoms, including global developmental delay, intellectual disability, childhood-onset epilepsy, dyspraxia, and speech deficits. We also identified two individuals with de novo missense variants in CDKL1 in the published Deciphering Developmental Disorders (DDD) and GeneDx cohorts with developmental disorders. Drosophila has a single ortholog of CDKL1-5, CG7236 (Cdkl). Cdkl is expressed in sensory neurons that project to specific regions of the brain that control sensory inputs. Cdkl loss causes semi-lethality, climbing defects, heat-induced seizures, hearing loss, and reduced lifespan. These phenotypes can be rescued by expression of the human reference CDKL1, CDKL2, or CDKL5, showing that the functions of these genes are conserved. In contrast, the CDKL1 and CDKL2 variants do not fully rescue the observed phenotypes, and overexpression of the variant proteins leads to phenotypes that are similar to Cdkl loss. Co-expression of CDKL1 or CDKL2 variants with CDKL1, CDKL2, or CDKL5 references in the mutant background suppresses the rescue ability of the reference genes. Our results suggest that the variants act as dominant negative alleles and are causative of neurological symptoms in these individuals.
Details
- Title: Subtitle
- De novo variants in CDKL1 and CDKL2 are associated with neurodevelopmental symptoms
- Creators
- Ali H Bereshneh - Texas Children's HospitalJonathan C Andrews - Baylor College of MedicineDaniel F Eberl - University of IowaGuney Bademci - Dr. John T. Macdonald FoundationNicholas A Borja - Dr. John T. Macdonald FoundationStephanie Bivona - Dr. John T. Macdonald FoundationWendy K Chung - Boston Children's HospitalShinya Yamamoto - Texas Children's HospitalMichael F Wangler - Baylor College of MedicineShane McKee - Belfast City HospitalMustafa Tekin - University of MiamiHugo J Bellen - Baylor College of MedicineOguz Kanca - Texas Children's HospitalUndiagnosed Diseases Network, Baylor College of Medicine Center for Precision Medicine Models
- Resource Type
- Journal article
- Publication Details
- American journal of human genetics, Vol.112(4), pp.846-862
- DOI
- 10.1016/j.ajhg.2025.02.019
- PMID
- 40088891
- PMCID
- PMC12081231
- NLM abbreviation
- Am J Hum Genet
- ISSN
- 1537-6605
- eISSN
- 1537-6605
- Publisher
- CELL PRESS; CAMBRIDGE
- Grant note
- Wellcome Trust: WT223718/Z/21/Z National Institutes of Health: R01-GM129325 Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious DiseasesHuffington FoundationJan and Dan Duncan Neurological Research Institute at Texas Children's HospitalSouthern Star Medical Research InstituteOffice of Research Infrastructure Programs of the National Institutes of Health: R24OD031447, U54OD030165, R24OD022005, U54NS093793, U2CNS132415-01S01 NSF: 2037828
The authors thank the individuals and families for their participa-tion in this study. The authors thank Hongling Pan for the trans-genic fly line, Liwen Ma and Ye-Jin Park for helping with fly tissue dissection and preparation, Megan Cooper for helping with west-ern blot, and Mingxi Deng for helping with protein structure pre-dictions. The authors thank the Bloomington Drosophila Stock Center for fly stocks and the Developmental Studies Hybridoma Bank for antibodies. This study makes use of data generated by the DECIPHER community. A full list of centers who contributed to the generation of the data is available from https://deciphergenomics.org/about/stats and via email from contact@ deciphergenomics.org. DECIPHER is hosted by EMBL-EBI and funding for the DECIPHER project was provided by the Wellcome Trust (grant no. WT223718/Z/21/Z) . Molecular graphics and ana-lyses were performed with UCSF ChimeraX, developed by the Resource for Biocomputing, Visualization, and Informatics at the University of California, San Francisco, with support from National Institutes of Health R01-GM129325 and the Office of Cyber Infrastructure and Computational Biology, National Institute of Allergy and Infectious Diseases. This work was supported by the Huffington Foundation; the Jan and Dan Duncan Neurological Research Institute at Texas Children's Hospital; Southern Star Medical Research Institute; and the Office of Research Infrastructure Programs of the National Institutes of Health R24OD031447 (O.K. and H.J.B.) , U54OD030165 (O.K. and S.Y.) , R24OD022005 (S.Y. and H.J.B.) , U54OD030165 (M.F.W. and H.J.B.) , U54NS093793 (S.Y., M.F.W., and H.J.B.) , and U2CNS132415-01S01 (S.Y., M.F.W., H.J.B., and O.K.) ; and NSF 2037828 (D.F.E.) .
- Language
- English
- Electronic publication date
- 03/11/2025
- Date published
- 04/2025
- Academic Unit
- Iowa Neuroscience Institute; Biology
- Record Identifier
- 9984801694402771
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