Identification of a KDM6A somatic mutation responsible for Kabuki syndrome by excluding a conflicting KMT2D germline variant through episignature analysis |
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| Affiliation: | 1. Department of Maternal-Fetal Biology, Research Institute, National Center for Child Health and Development, Setagaya, Tokyo, 157-8535, Japan;2. Department of Pediatrics, Tokyo Metropolitan Tobu Medical Center for Children with Developmental Disabilities, Koto, Tokyo, 136-0075, Japan;3. Department of Pharmacology, Research Institute, National Center for Child Health and Development, Setagaya, Tokyo, 157-8535, Japan;4. Department of Human Molecular Genetics, Gunma University Graduate School of Medicine, Maebashi, Gunma, 371-8511, Japan;5. Department of Child Health, Tokyo Kasei University, Itabashi, Tokyo, 173-8602, Japan;1. The Steve and Cindy Rasmussen Institute for Genomic Medicine, Nationwide Children''s Hospital, Columbus, OH, USA;2. Departments of Pathology, Departments of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA;3. Division of Pediatric Neurology, Renown Children''s Hospital, Reno, NV, USA;4. University of Nevada, Reno School of Medicine, Reno, NV, USA;5. MRC Human Genetics Unit, Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, UK;6. Division of Hospital Medicine, Nationwide Children''s Hospital, Columbus, OH, USA;7. Department of Radiology, Nationwide Children''s Hospital, Columbus, OH, USA;8. The Ohio State University College of Medicine, Columbus, OH, 43210, USA;9. Division of Pediatric Neurology, Nationwide Children''s Hospital, Columbus, OH, USA;10. Laboratory of Neurogenetics and Neuroinflammation, Institut Imagine, Université de Paris, Paris, France;11. Division of Genetic and Genomic Medicine, Nationwide Children''s Hospital, Columbus, OH, USA;1. Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark;2. Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark;3. Centre for Rare Diseases, Pediatrics and Adolescent Medicine, Aarhus University Hospital, Aarhus, Denmark;1. Department of Physiology, Institute of Biomedicine and Translational Medicine, Faculty of Medicine, University of Tartu, Tartu, Estonia;2. Department of Clinical Genetics, Karolinska University Hospital, Stockholm, Sweden;3. Laboratory for Human Genetics, University of Sarajevo - Institute for Genetic Engineering and Biotechnology, Sarajevo, Bosnia and Herzegovina;4. Department of Psychiatry, University of Szeged, Szeged, Hungary;5. Department of Medical Epidemiology and Biostatistics, Karolinska Institute, Stockholm, Sweden;6. Pathology Department, Faculty of Medicine and Surgery, University of Malta, Msida, Malta;7. University of Zagreb School of Medicine, Department of Pharmacology, Zagreb, Croatia;8. Laboratory of Human Genetics, IRCCS Istituto Giannina Gaslini, Genoa, Italy;9. Department of Child and Adolescent Psychiatry, Psychosomatics and Psychotherapy, University Hospital Essen, University of Duisburg-Essen, Essen, Germany;10. University Hospital Centre Zagreb, Department of Laboratory Diagnostics, Division for Pharmacogenomics and Therapy Individualization, Zagreb, Croatia;11. Department of Clinical Genetics, Aarhus University Hospital, Aarhus, Denmark;12. Université Paris Cité, INSERM U1266, Institute of Psychiatry and Neuroscience of Paris, Paris, France;13. Faculté de Médecine-Sorbonne Université, Groupe de Recherche Clinique N°15 - Troubles Psychiatriques et Développement (PSYDEV) & Centre de Référence des Maladies Rares à Expression Psychiatrique, DMU ORYGINE Femmes-Mères-Enfants, Service de Psychiatrie de l’Enfant et de l’Adolescent, Assistance Publique-Hôpitaux de Paris, Sorbonne Université, Paris, France;14. Molecular Psychiatry Laboratory, Division of Psychiatry, University College London, London, UK;15. Psychiatric Clinic, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania;p. Centre for Molecular Medicine and Biobanking, University of Malta, Malta;q. Center for Predictive and Preventive Genetics, Institute of Molecular and Cellular Biology, Institute for Research and Innovation in Health, University of Porto, Porto, Portugal;r. Department of Genetic Epidemiology in Psychiatry, Central Institute of Mental Health, Medical Faculty Mannheim, Heidelberg University, Germany;s. Alexandru Obregia Clinical Psychiatric Hospital, Biometric Psychiatric Genetics Research Unit, Bucharest, Romania;t. Department of Clinical Genetics, Karolinska University Hospital, Stockholm and Karolinska Institutet, Stockholm, Sweden;u. Finnish Institute for Health and Welfare, Department of Public Health and Welfare, Mental Health Team, Helsinki, Finland;v. Department of Human and Medical Genetics, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, Vilnius, Lithuania;w. Department of Psychiatry, University of Münster, Münster, Germany;x. Medical Genetic Institute, Shaare Zedek Medical Center, Jerusalem, Israel;y. Université Paris Cité, INSERM U1266, Institute of Psychiatry and Neuroscience of Paris, GHU-Paris Psychiatrie et Neurosciences, Paris, France;z. Center of Neurodevelopmental Disorders (KIND), Centre for Psychiatry Research, Department of Women''s and Children''s Health, Karolinska Institute, Region Stockholm, Stockholm, Sweden;11. Astrid Lindgren Children''s Hospital, Karolinska University Hospital, Region Stockholm, Stockholm, Sweden;12. Department of Psychiatry, McGill University, Montreal, Canada;13. Center for Research and Bioethics, CRB, Uppsala University, Uppsala, Sweden;1. Department of Public Health and Primary Care, KU Leuven, Leuven, Belgium;2. Melbourne Law School, University of Melbourne, Melbourne, Australia;3. Murdoch Children''s Research Institute, Melbourne, Australia;1. Birmingham Women''s and Children''s NHS Foundation Trust, Clinical Genetics Department, Birmingham, Birmingham, UK;2. Leeds Teaching Hospitals NHS Trust, North East and Yorkshire Genomic Laboratory Hub Central Laboratory, Ashley Wing, St James''s University Hospital, Leeds, UK;3. Birmingham Women''s and Children''s NHS Foundation Trust, Radiology Department, Birmingham Children''s Hospital, Steelhouse Lane, Birmingham, UK;1. UF de Génomique du Développement, Département de Génétique médicale, Groupe Hospitalier Pitié-Salpêtrière, AP-HP Sorbonne Université, Paris, France;2. Service de Médecine Génomique des maladies rares, UF MP5, Hôpital Necker-Enfants Malades, AP-HP Université Paris Cité, Paris, France;3. UF de Foetopathologie, CHR d’Orléans, Orléans, France;4. Service de Foetopathologie, Hôpital Armand Trousseau, AP-HP Sorbonne Université, Paris, France;5. UF de Génétique Médicale et CRMR « Déficience intellectuelle », Département de Génétique médicale, Groupe Hospitalier Pitié-Salpêtrière, AP-HP Sorbonne Université, Paris, France;6. Laboratoire de Biologie Médicale Multisites SeqOIA, Paris, France;7. Gynécologie obstétrique, Hôpital Trousseau, Centre de Référence C-MAVEM, AP-HP Sorbonne Université, Paris, France;8. Service de Radiologie Pédiatrique, Hôpital Trousseau, AP-HP Sorbonne Université, Paris, France;9. Service de Neurologie Pédiatrique, Hôpital Trousseau, AP-HP Sorbonne Université, Paris, France;10. UF de Génomique Chromosomique, Département de Génétique médicale, Hôpital Armand Trousseau, AP-HP Sorbonne Université, Paris, France |
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| Abstract: | Kabuki syndrome (KS) is a congenital disorder caused by mutations in either KMT2D on chromosome 12 or KDM6A on chromosome X, encoding a lysine methyltransferase and a lysine demethylase, respectively. A 9-year-4-month-old male patient with a normal karyotype presented with KS and autism spectrum disorder. Genetic testing for KS was conducted by Sanger sequencing and episignature analysis using DNA methylation array data. The patient had a mosaic stop-gain variant in KDM6A and a heterozygous missense variant (rs201078160) in KMT2D. The KDM6A variant is expected to be deleterious. The KMT2D variant pathogenicity has been inconsistently reported in the ClinVar database. Using biobanking resources, we identified two heterozygous individuals possessing the rs201078160 variant. In a subsequent episignature analysis, the KS patient showed the KS episignature, but two control individuals with the rs201078160 variant did not. Our results indicate that the mosaic stop-gained variant in KDM6A, but not the rs201078160 variant in KMT2D, is responsible for the KS phenotype in the patient. This study further demonstrated the utility of DNA methylation information in diagnosing rare genetic diseases and emphasized the importance of a reference dataset containing both genotype and DNA methylation information. |
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| Keywords: | kabuki syndrome DNA methylation Episignature |
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