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Title: CDK13-related disorder: Report of a series of 18 previously unpublished individuals and description of an epigenetic signature.
Austin Authors: Rouxel, Flavien;Relator, Raissa;Kerkhof, Jennifer;McConkey, Haley;Levy, Michael;Dias, Patricia;Barat-Houari, Mouna;Bednarek, Nathalie;Boute, Odile;Chatron, Nicolas;Cherik, Florian;Delahaye-Duriez, Andrée;Doco-Fenzy, Martine;Faivre, Laurence;Gauthier, Lucas W;Heron, Delphine;Hildebrand, Michael S ;Lesca, Gaëtan;Lespinasse, James;Mazel, Benoit;Menke, Leonie A;Morgan, Angela T;Pinson, Lucile;Quelin, Chloe;Rossi, Massimiliano;Ruiz-Pallares, Nathalie;Tran-Mau-Them, Frederic;Van Kessel, Imke N;Vincent, Marie;Weber, Mathys;Willems, Marjolaine;Leguyader, Gwenael;Sadikovic, Bekim;Genevieve, David
Affiliation: Epilepsy Research Centre
Murdoch Children's Research Institute, Department of Audiology and Speech Pathology, University of Melbourne, Melbourne, Victoria, Australia
Department of Audiology and Speech Pathology, Melbourne School of Health Sciences, The University of Melbourne, Parkville, Victoria, Australia
Genetics Department, Hospital Center of Lisbon North, ERN ITHACA, Lisbon, Portugal
Genetics Department, CHU Reims, Medical school IFR53, EA3801, Reims, France
Genetics Department, Guy Fontaine Medical Center, CLAD Nord de France, Jeanne de Flandre Hospital, CHRU Lille, Lille, France
Genetics Department, Lyon University Hospital, and Institut NeuroMyoGène, CNRS UMR 5310 - INSERM U1217, Claude Bernard Lyon 1 University, Lyon, France
Genetics Department, CHU Clermont-Ferrand, Clermont-Ferrand, France
PROTECT, INSERM, Paris Diderot University, Paris, France
Genetics Department, University Hospital Pitié-Salpétrière, Paris, France
Chromosomic genetic laboratory, CH Général, Chambéry, France
Génétique clinique, Département de Génétique Médicale, Maladies Rares et Médecine Personnalisée, CHU Montpellier, Montpellier University, Centre de Référence Anomalies du Développement SOOR, INSERM U1183, ERN ITHACA, Montpellier, France
Department of Clinical Genetics, CLAD Ouest, CHU de Rennes, Hôpital Sud, Rennes, France
Département de Génétique Médicale, Maladies Rares et Médecine Personnalisée, Génétique des Maladies Rares et Auto-Inflammatoires, CHU Montpellier, Université de Montpellier, Montpellier, France
Department of Pediatrics, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, ERN ITHACA, Amsterdam, Netherlands
Genetics Department, CHU de Nantes, Nantes, France
Centre de Référence Anomalies du Développement et Syndromes Malformatifs, FHU TRANSLAD, CHU Dijon, Dijon, France
Genetics Department, CHU de Poitiers, Poitiers University Hospital, Poitiers, France
Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada
The Archie & Irene Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, Ontario, Canada
Paris 13 University, Sorbonne Paris Cité, UFR SMBH Bobigny
Genetics Department, Referral Centre for Developmental Abnormalities, Lyon University Hospital Lyon, France
Genetics of Developmental Disorders, INSERM - Bourgogne Franche-Comté University, UMR 1231 GAD Team, Dijon, France
INSERM U1028, CNRS UMR5292, Lyon Neuroscience Research Centre, GENDEV Team, Claude Bernard Lyon 1 University, Lyon, France
Functional Unit 6254 Innovation in Genomic Diagnosis of Rare Diseases, CHU Dijon Bourgogne, Dijon, France
Issue Date: May-2022
Date: 2022-01-19
Publication information: Genetics in Medicine 2022; 24(5): 1096-1107
Abstract: 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. 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. 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. 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.
DOI: 10.1016/j.gim.2021.12.016
ORCID: 0000-0003-2739-0515
Journal: Genetics in Medicine : Official Journal of the American College of Medical Genetics
PubMed URL: 35063350
PubMed URL:
Type: Journal Article
Subjects: CDK13
Appears in Collections:Journal articles

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