Update of the genotype and phenotype of KMT2D and KDM6A by genetic screening of 100 patients with clinically suspected Kabuki syndrome

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 YamaguchiMasahisa Kobayashi, Makiko Tominaga, Satoshi Ishikiriyama, Toshiaki Tanaka, Hiroshi Suzumura, Shinsuke Ninomiya, Akane Kondo, Tadashi Kaname, Kenjiro Kosaki, Mitsuo Masuno, Yoshikazu Kuroki, Kenji Kurosawa

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

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.

Original languageEnglish
Pages (from-to)2333-2344
Number of pages12
JournalAmerican Journal of Medical Genetics, Part A
Volume182
Issue number10
DOIs
Publication statusPublished - 2020 Oct 1

Keywords

  • blended phenotype
  • deep splicing variant
  • Kabuki syndrome
  • malignancy
  • mosaicism

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

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