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Update of the genotype and phenotype of KMT2D and KDM6A by genetic screening of 100 patients with clinically suspected Kabuki syndrome |
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| Authors: | Hiroaki Murakami Yoshinori Tsurusaki Keisuke Enomoto Yukiko Kuroda Takayuki Yokoi Noritaka Furuya Hiroshi Yoshihashi Mari Minatogawa Chihiro Abe‐Hatano Ikuko Ohashi Naoto Nishimura Tatsuro Kumaki Yumi Enomoto Takuya Naruto Fuminori Iwasaki Noriaki Harada Aki Ishikawa Hiroshi Kawame Kiyoko Sameshima Yu Yamaguchi Masahisa Kobayashi Makiko Tominaga Satoshi Ishikiriyama Toshiaki Tanaka Hiroshi Suzumura Shinsuke Ninomiya Akane Kondo Tadashi Kaname Kenjiro Kosaki Mitsuo Masuno Yoshikazu Kuroki Kenji Kurosawa |
| Institution: | 1. https://orcid.org/0000-0002-6646-6263;2. Division of Medical Genetics, Kanagawa Children's Medical Center, Yokohama, Japan;3. Hiroaki Murakami and Kenji Kurosawa, Division of Medical Genetics, Kanagawa Children's Medical Center, 2‐138‐4 Mutsukawa, Minami‐ku, Yokohama 232‐8555, Japan.;4. Email: (H. M.) and (K. K.);5. Clinical Research Institute, Kanagawa Children's Medical Center, Yokohama, Japan;6. Division of Hematology/Oncology, Kanagawa Children's Medical Center, Yokohama, Japan;7. Department of Clinical Laboratory, Kanagawa Children's Medical Center, Yokohama, Japan;8. Department of Medical Genetics and Genomics, Sapporo Medical University School of Medicine, Sapporo, Japan;9. Graduate School of Medicine, Tohoku University, Sendai, Japan;10. Division of Medical Genetics, Gunma Children's Medical Center, Gunma, Japan;11. Department of Pediatrics, Jikei University School of Medicine, Tokyo, Japan;12. Children's Medical Center, Northern Yokohama Hospital, Showa University, Yokohama, Japan;13. Division of Clinical Genetics and Cytogenetics, Shizuoka Children's Hospital, Shizuoka, Japan;14. Tanaka Growth Clinic, Tokyo, Japan;15. Department of Pediatrics, Dokkyo Medical University, Tochigi, Japan;16. Department of Clinical Genetics, Kurashiki Central Hospital, Kurashiki, Japan;17. Department of Gynecology, Shikoku Medical Center for Children and Adults, Kagawa, Japan;18. Department of Genome Medicine, National Center for Child Health and Development, Tokyo, Japan;19. Center for Medical Genetics, Keio University School of Medicine, Tokyo, Japan;20. Genetic Counseling Program, Graduate School of Health and Welfare, Kawasaki University of Medical Welfare, Kurashiki, Japan;21. |
| Abstract: | Kabuki syndrome is characterized by a variable degree of intellectual disability, characteristic facial features, and complications in various organs. Many variants have been identified in two causative genes, that is, lysine methyltransferase 2D (KMT2D) and lysine demethylase 6A (KDM6A). In this study, we present the results of genetic screening of 100 patients with a suspected diagnosis of Kabuki syndrome in our center from July 2010 to June 2018. We identified 76 variants (43 novel) in KMT2D and 4 variants (3 novel) in KDM6A as pathogenic or likely pathogenic. Rare variants included a deep splicing variant (c.14000‐8C>G) confirmed by RNA sequencing and an 18% mosaicism level for a KMT2D mutation. We also characterized a case with a blended phenotype consisting of Kabuki syndrome, osteogenesis imperfecta, and 16p13.11 microdeletion. We summarized the clinical phenotypes of 44 patients including a patient who developed cervical cancer of unknown origin at 16 years of age. This study presents important details of patients with Kabuki syndrome including rare clinical cases and expands our genetic understanding of this syndrome, which will help clinicians and researchers better manage and understand patients with Kabuki syndrome they may encounter. |
| Keywords: | blended phenotype deep splicing variant Kabuki syndrome malignancy mosaicism |