title: MLL2 and KDM6A mutations in patients with Kabuki syndrome.
abstract: Kabuki syndrome is a congenital anomaly syndrome characterized by developmental delay, intellectual disability, specific facial features including long palpebral fissures and ectropion of the lateral third of the lower eyelids, prominent digit pads, and skeletal and visceral abnormalities. Mutations in MLL2 and KDM6A cause Kabuki syndrome. We screened 81 individuals with Kabuki syndrome for mutations in these genes by conventional methods (n = 58) and/or targeted resequencing (n = 45) or whole exome sequencing (n = 5). We identified a mutation in MLL2 or KDM6A in 50 (61.7%) and 5 (6.2%) cases, respectively. Thirty-five MLL2 mutations and two KDM6A mutations were novel. Non-protein truncating-type MLL2 mutations were mainly located around functional domains, while truncating-type mutations were scattered through the entire coding region. The facial features of patients in the MLL2 truncating-type mutation group were typical based on those of the 10 originally reported patients with Kabuki syndrome; those of the other groups were less typical. High arched eyebrows, short fifth finger, and hypotonia in infancy were more frequent in the MLL2 mutation group than in the KDM6A mutation group. Short stature and postnatal growth retardation were observed in all individuals with KDM6A mutations, but in only half of the group with MLL2 mutations.
authors.affiliation: Department of Human Genetics, Yokohama City University Graduate School of Medicine, Yokohama, Japan. nmiyake@yokohama-cu.ac.jp
authors.forename: Noriko
authors.initials: N
authors.lastname: Miyake
authors.forename: Eriko
authors.initials: E
authors.lastname: Koshimizu
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Okamoto
authors.forename: Seiji
authors.initials: S
authors.lastname: Mizuno
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Ogata
authors.forename: Toshiro
authors.initials: T
authors.lastname: Nagai
authors.forename: Tomoki
authors.initials: T
authors.lastname: Kosho
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Ohashi
authors.forename: Mitsuhiro
authors.initials: M
authors.lastname: Kato
authors.forename: Goro
authors.initials: G
authors.lastname: Sasaki
authors.forename: Hiroyo
authors.initials: H
authors.lastname: Mabe
authors.forename: Yoriko
authors.initials: Y
authors.lastname: Watanabe
authors.forename: Makoto
authors.initials: M
authors.lastname: Yoshino
authors.forename: Toyojiro
authors.initials: T
authors.lastname: Matsuishi
authors.forename: Jun-ichi
authors.initials: J
authors.lastname: Takanashi
authors.forename: Vorasuk
authors.initials: V
authors.lastname: Shotelersuk
authors.forename: Mustafa
authors.initials: M
authors.lastname: Tekin
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Ochi
authors.forename: Masaya
authors.initials: M
authors.lastname: Kubota
authors.forename: Naoko
authors.initials: N
authors.lastname: Ito
authors.forename: Kenji
authors.initials: K
authors.lastname: Ihara
authors.forename: Toshiro
authors.initials: T
authors.lastname: Hara
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Tonoki
authors.forename: Tohru
authors.initials: T
authors.lastname: Ohta
authors.forename: Kayoko
authors.initials: K
authors.lastname: Saito
authors.forename: Mari
authors.initials: M
authors.lastname: Matsuo
authors.forename: Mari
authors.initials: M
authors.lastname: Urano
authors.forename: Takashi
authors.initials: T
authors.lastname: Enokizono
authors.forename: Astushi
authors.initials: A
authors.lastname: Sato
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Tanaka
authors.forename: Atsushi
authors.initials: A
authors.lastname: Ogawa
authors.forename: Takako
authors.initials: T
authors.lastname: Fujita
authors.forename: Yoko
authors.initials: Y
authors.lastname: Hiraki
authors.forename: Sachiko
authors.initials: S
authors.lastname: Kitanaka
authors.forename: Yoichi
authors.initials: Y
authors.lastname: Matsubara
authors.forename: Toshio
authors.initials: T
authors.lastname: Makita
authors.forename: Masataka
authors.initials: M
authors.lastname: Taguri
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Nakashima
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Tsurusaki
authors.forename: Hirotomo
authors.initials: H
authors.lastname: Saitsu
authors.forename: Ko-ichiro
authors.initials: K
authors.lastname: Yoshiura
authors.forename: Naomichi
authors.initials: N
authors.lastname: Matsumoto
authors.forename: Norio
authors.initials: N
authors.lastname: Niikawa
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics*; D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution; D002648:Child; D002675:Child, Preschool; D004268:DNA-Binding Proteins / Q000235:genetics*; D059472:Exome; D005145:Face / Q000002:abnormalities*; D019066:Facies; D005260:Female; D056726:Genetic Association Studies; D006402:Hematologic Diseases / Q000175:diagnosis / Q000235:genetics*; D059014:High-Throughput Nucleotide Sequencing; D056466:Histone Demethylases / Q000235:genetics*; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D009154:Mutation; D059645:Mutation Rate; D009363:Neoplasm Proteins / Q000235:genetics*; D009687:Nuclear Proteins / Q000235:genetics*; D010641:Phenotype; D015837:Vestibular Diseases / Q000175:diagnosis / Q000235:genetics*; D049951:X Chromosome Inactivation; D055815:Young Adult
chemical_list: D004268:DNA-Binding Proteins; C120898:KMT2D protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D056466:Histone Demethylases; C523998:KDM6A protein, human
keywords: KDM6A; Kabuki syndrome; MLL2; genotype-phenotype correlation; mutation