CDK13-related disorder: Report of a series of 18 previously unpublished individuals and description of an epigenetic signature

Flavien Rouxel, Raissa Relator, Jennifer Kerkhof, Haley McConkey, Michael Levy, Patricia Dias, Mouna Barat-Houari, Nathalie Bednarek, Odile Boute, Nicolas Chatron, Florian Cherik, Andrée Delahaye-Duriez, Martine Doco-Fenzy, Laurence Faivre, Lucas W. Gauthier, Delphine Heron, Michael S. Hildebrand, Gaëtan Lesca, James Lespinasse, Benoit MazelLeonie A. Menke, Angela T. Morgan, Lucile Pinson, Chloe Quelin, Massimiliano Rossi, Nathalie Ruiz-Pallares, Frederic Tran-Mau-Them, Imke N. van Kessel, Marie Vincent, Mathys Weber, Marjolaine Willems, Gwenael Leguyader, Bekim Sadikovic*, David Genevieve*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review


Purpose: Rare genetic variants in CDK13 are responsible for CDK13-related disorder (CDK13-RD), with main clinical features being developmental delay or intellectual disability, facial features, behavioral problems, congenital heart defect, and seizures. In this paper, we report 18 novel individuals with CDK13-RD and provide characterization of genome-wide DNA methylation. Methods: We obtained clinical phenotype and neuropsychological data for 18 and 10 individuals, respectively, and compared this series with the literature. We also compared peripheral blood DNA methylation profiles in individuals with CDK13-RD, controls, and other neurodevelopmental disorders episignatures. Finally, we developed a support vector machine–based classifier distinguishing CDK13-RD and non–CDK13-RD samples. Results: We reported health and developmental parameters, clinical data, and neuropsychological profile of individuals with CDK13-RD. Genome-wide differential methylation analysis revealed a global hypomethylated profile in individuals with CDK13-RD in a highly sensitive and specific model that could aid in reclassifying variants of uncertain significance. Conclusion: We describe the novel features such as anxiety disorder, cryptorchidism, and disrupted sleep in CDK13-RD. We define a CDK13-RD DNA methylation episignature as a diagnostic tool and a defining functional feature of the evolving clinical presentation of this disorder. We also show overlap of the CDK13 DNA methylation profile in an individual with a functionally and clinically related CCNK-related disorder.
Original languageEnglish
Pages (from-to)1096-1107
Number of pages12
JournalGenetics in Medicine
Issue number5
Publication statusPublished - 1 May 2022

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