CDK13-related disorder: Report of a series of 18 previously unpublished individuals and description of an epigenetic signature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

doi:10.1016/j.gim.2021.12.016

CDK13-related disorder: Report of a series of 18 previously unpublished individuals and description of an epigenetic signature

Genet Med. 2022 May;24(5):1096-1107. doi: 10.1016/j.gim.2021.12.016. Epub 2022 Jan 19.

Authors

Flavien Rouxel¹, Raissa Relator², Jennifer Kerkhof², Haley McConkey², Michael Levy², Patricia Dias³, Mouna Barat-Houari⁴, Nathalie Bednarek⁵, Odile Boute⁶, Nicolas Chatron⁷, Florian Cherik⁸, Andrée Delahaye-Duriez⁹, Martine Doco-Fenzy⁵, Laurence Faivre¹⁰, Lucas W Gauthier⁷, Delphine Heron¹¹, Michael S Hildebrand¹², Gaëtan Lesca⁷, James Lespinasse¹³, Benoit Mazel¹⁴, Leonie A Menke¹⁵, Angela T Morgan¹⁶, Lucile Pinson¹, Chloe Quelin¹⁷, Massimiliano Rossi¹⁸, Nathalie Ruiz-Pallares⁴, Frederic Tran-Mau-Them¹⁹, Imke N Van Kessel¹⁵, Marie Vincent²⁰, Mathys Weber¹⁴, Marjolaine Willems¹, Gwenael Leguyader²¹, Bekim Sadikovic²², David Genevieve²³

Affiliations

¹ 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.
² The Archie & Irene Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, Ontario, Canada.
³ Genetics Department, Hospital Center of Lisbon North, ERN ITHACA, Lisbon, Portugal.
⁴ Département de Génétique Médicale, Maladies Rares et Médecine Personnalisée, Génétique des Maladies Rares et Auto-Inflammatoires, CHU Montpellier, Université de Montpellier, Montpellier, France.
⁵ Genetics Department, CHU Reims, Medical school IFR53, EA3801, Reims, France.
⁶ Genetics Department, Guy Fontaine Medical Center, CLAD Nord de France, Jeanne de Flandre Hospital, CHRU Lille, Lille, France.
⁷ Genetics Department, Lyon University Hospital, and Institut NeuroMyoGène, CNRS UMR 5310 - INSERM U1217, Claude Bernard Lyon 1 University, Lyon, France.
⁸ Genetics Department, CHU Clermont-Ferrand, Clermont-Ferrand, France.
⁹ Department of Histology Embryology and Cytogenetics, Jean Verdier Hospital; Paris 13 University, Sorbonne Paris Cité, UFR SMBH Bobigny; PROTECT, INSERM, Paris Diderot University, Paris, France.
¹⁰ Centre de Référence Anomalies du Développement et Syndromes Malformatifs, FHU TRANSLAD, CHU Dijon, Dijon, France; Genetics of Developmental Disorders, INSERM - Bourgogne Franche-Comté University, UMR 1231 GAD Team, Dijon, France.
¹¹ Genetics Department, University Hospital Pitié-Salpétrière, Paris, France.
¹² Epilepsy Research Center, Department of Medicine, Austin Health, The University of Melbourne, Heidelberg, Victoria, Australia; Murdoch Children's Research Institute, Department of Audiology and Speech Pathology, University of Melbourne, Melbourne, Victoria, Australia.
¹³ Chromosomic genetic laboratory, CH Général, Chambéry, France.
¹⁴ Centre de Référence Anomalies du Développement et Syndromes Malformatifs, FHU TRANSLAD, CHU Dijon, Dijon, France.
¹⁵ Department of Pediatrics, Emma Children's Hospital, Amsterdam UMC, University of Amsterdam, ERN ITHACA, Amsterdam, Netherlands.
¹⁶ Department of Audiology and Speech Pathology, Melbourne School of Health Sciences, The University of Melbourne, Parkville, Victoria, Australia.
¹⁷ Department of Clinical Genetics, CLAD Ouest, CHU de Rennes, Hôpital Sud, Rennes, France.
¹⁸ Genetics Department, Lyon University Hospital, and Institut NeuroMyoGène, CNRS UMR 5310 - INSERM U1217, Claude Bernard Lyon 1 University, Lyon, France; Genetics Department, Referral Centre for Developmental Abnormalities, Lyon University Hospital Lyon, France; INSERM U1028, CNRS UMR5292, Lyon Neuroscience Research Centre, GENDEV Team, Claude Bernard Lyon 1 University, Lyon, France.
¹⁹ Genetics of Developmental Disorders, INSERM - Bourgogne Franche-Comté University, UMR 1231 GAD Team, Dijon, France; Functional Unit 6254 Innovation in Genomic Diagnosis of Rare Diseases, CHU Dijon Bourgogne, Dijon, France.
²⁰ Genetics Department, CHU de Nantes, Nantes, France.
²¹ Genetics Department, CHU de Poitiers, Poitiers University Hospital, Poitiers, France.
²² The Archie & Irene Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, Ontario, Canada; Department of Pathology and Laboratory Medicine, Western University, London, Ontario, Canada. Electronic address: [email protected].
²³ 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. Electronic address: [email protected].

PMID: 35063350
DOI: 10.1016/j.gim.2021.12.016

Abstract

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.

Keywords: CDK13; CHDFIDD; Clinical; Epigenetic; Signature.

MeSH terms

CDC2 Protein Kinase / genetics
DNA Methylation / genetics
Epigenesis, Genetic / genetics
Humans
Intellectual Disability* / diagnosis
Intellectual Disability* / genetics
Male
Neurodevelopmental Disorders* / genetics
Phenotype

Substances

CDC2 Protein Kinase
CDK13 protein, human