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DNA methylation episignature testing improves molecular diagnosis of Mendelian chromatinopathies |
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| Authors: | Jennifer Kerkhof Gabriella Maria Squeo Haley McConkey Michael A Levy Maria Rosaria Piemontese Marco Castori Maria Accadia Elisa Biamino Matteo Della Monica Marilena Carmela Di Giacomo Cristina Gervasini Silvia Maitz Daniela Melis Donatella Milani Maria Piccione Paolo Prontera Angelo Selicorni Bekim Sadikovic Giuseppe Merla |
| Institution: | 1. Molecular Diagnostics Program, and Verspeeten Clinical Genome Centre, London Health Sciences Centre, London, Canada;2. Laboratory of Regulatory and Functional Genomics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (Foggia), Italy;3. Division of Medical Genetics, Fondazione IRCCS Casa Sollievo della Sofferenza, San Giovanni Rotondo (Foggia), Italy;4. Medical Genetics Service, Hospital “Cardinale G. Panico”, Tricase, Lecce, Italy;5. Department of Pediatrics, University of Turin, Italy;6. Medical Genetics Unit, Cardarelli Hospital, Largo A Cardarelli, Napoli, Italy;7. UOC Anatomia Patologica, AOR “San Carlo”, Hospital Potenza, Italy;8. Division of Medical Genetics, Department of Health Sciences, Università degli Studi di Milano, Milan, Italy;9. Clinical Pediatric Genetics Unit, Pediatrics Clinics, MBBM Foundation, Hospital San Gerardo, Monza, Italy;10. Medical, Surgical, and Dental Department, Università degli Studi di Salerno, Salerno, Italy;11. Fondazione IRCCS Ca'' Granda Ospedale Maggiore Policlinico, Milan, Italy;12. Medical Genetics Unit Department of Health Promotion, Mother and Child Care, Internal Medicine and Medical Specialties, University of Palermo, Palermo, Italy;13. Medical Genetics Unit, University of Perugia Hospital SM della Misericordia, Perugia, Italy;14. Pediatric Department, ASST Lariana, Sant''Anna General Hospital, Como, Italy;15. Department of Pathology and Laboratory Medicine, Western University, London, Canada;16. Department of Molecular Medicine and Medical Biotechnology, University of Naples Federico II, Via S. Pansini 5, 80131 Naples, Italy |
| Abstract: | PurposeChromatinopathies include more than 50 disorders caused by disease-causing variants of various components of chromatin structure and function. Many of these disorders exhibit unique genome-wide DNA methylation profiles, known as episignatures. In this study, the methylation profile of a large cohort of individuals with chromatinopathies was analyzed for episignature detection.MethodsDNA methylation data was generated on extracted blood samples from 129 affected individuals with the Illumina Infinium EPIC arrays and analyzed using an established bioinformatic pipeline.ResultsThe DNA methylation profiles matched and confirmed the sequence findings in both the discovery and validation cohorts. Twenty-five affected individuals carrying a variant of uncertain significance, did not show a methylation profile matching any of the known episignatures. Three additional variant of uncertain significance cases with an identified KDM6A variant were re-classified as likely pathogenic (n = 2) or re-assigned as Wolf-Hirschhorn syndrome (n = 1). Thirty of the 33 Next Generation Sequencing negative cases did not match a defined episignature while three matched Kabuki syndrome, Rubinstein-Taybi syndrome and BAFopathy respectively.ConclusionWith the expanding clinical utility of the EpiSign assay, DNA methylation analysis should be considered part of the testing cascade for individuals presenting with clinical features of Mendelian chromatinopathy disorders. |
| Keywords: | DNA methylation Chromatinopathies Epigenetics |
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