title: Spectrum of MLL2 (ALR) mutations in 110 cases of Kabuki syndrome.
abstract: Kabuki syndrome is a rare, multiple malformation disorder characterized by a distinctive facial appearance, cardiac anomalies, skeletal abnormalities, and mild to moderate intellectual disability. Simplex cases make up the vast majority of the reported cases with Kabuki syndrome, but parent-to-child transmission in more than a half-dozen instances indicates that it is an autosomal dominant disorder. We recently reported that Kabuki syndrome is caused by mutations in MLL2, a gene that encodes a Trithorax-group histone methyltransferase, a protein important in the epigenetic control of active chromatin states. Here, we report on the screening of 110 families with Kabuki syndrome. MLL2 mutations were found in 81/110 (74%) of families. In simplex cases for which DNA was available from both parents, 25 mutations were confirmed to be de novo, while a transmitted MLL2 mutation was found in two of three familial cases. The majority of variants found to cause Kabuki syndrome were novel nonsense or frameshift mutations that are predicted to result in haploinsufficiency. The clinical characteristics of MLL2 mutation-positive cases did not differ significantly from MLL2 mutation-negative cases with the exception that renal anomalies were more common in MLL2 mutation-positive cases. These results are important for understanding the phenotypic consequences of MLL2 mutations for individuals and their families as well as for providing a basis for the identification of additional genes for Kabuki syndrome.
authors.affiliation: Department of Pediatrics, University of Washington, Seattle, 98195, USA.
authors.forename: Mark C
authors.initials: MC
authors.lastname: Hannibal
authors.forename: Kati J
authors.initials: KJ
authors.lastname: Buckingham
authors.forename: Sarah B
authors.initials: SB
authors.lastname: Ng
authors.forename: Jeffrey E
authors.initials: JE
authors.lastname: Ming
authors.forename: Anita E
authors.initials: AE
authors.lastname: Beck
authors.forename: Margaret J
authors.initials: MJ
authors.lastname: McMillin
authors.forename: Heidi I
authors.initials: HI
authors.lastname: Gildersleeve
authors.forename: Abigail W
authors.initials: AW
authors.lastname: Bigham
authors.forename: Holly K
authors.initials: HK
authors.lastname: Tabor
authors.forename: Heather C
authors.initials: HC
authors.lastname: Mefford
authors.forename: Joseph
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authors.lastname: Cook
authors.forename: Koh-ichiro
authors.initials: K
authors.lastname: Yoshiura
authors.forename: Tadashi
authors.initials: T
authors.lastname: Matsumoto
authors.forename: Naomichi
authors.initials: N
authors.lastname: Matsumoto
authors.forename: Noriko
authors.initials: N
authors.lastname: Miyake
authors.forename: Hidefumi
authors.initials: H
authors.lastname: Tonoki
authors.forename: Kenji
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authors.lastname: Naritomi
authors.forename: Tadashi
authors.initials: T
authors.lastname: Kaname
authors.forename: Toshiro
authors.initials: T
authors.lastname: Nagai
authors.forename: Hirofumi
authors.initials: H
authors.lastname: Ohashi
authors.forename: Kenji
authors.initials: K
authors.lastname: Kurosawa
authors.forename: Jia-Woei
authors.initials: JW
authors.lastname: Hou
authors.forename: Tohru
authors.initials: T
authors.lastname: Ohta
authors.forename: Deshung
authors.initials: D
authors.lastname: Liang
authors.forename: Akira
authors.initials: A
authors.lastname: Sudo
authors.forename: Colleen A
authors.initials: CA
authors.lastname: Morris
authors.forename: Siddharth
authors.initials: S
authors.lastname: Banka
authors.forename: Graeme C
authors.initials: GC
authors.lastname: Black
authors.forename: Jill
authors.initials: J
authors.lastname: Clayton-Smith
authors.forename: Deborah A
authors.initials: DA
authors.lastname: Nickerson
authors.forename: Elaine H
authors.initials: EH
authors.lastname: Zackai
authors.forename: Tamim H
authors.initials: TH
authors.lastname: Shaikh
authors.forename: Dian
authors.initials: D
authors.lastname: Donnai
authors.forename: Norio
authors.initials: N
authors.lastname: Niikawa
authors.forename: Jay
authors.initials: J
authors.lastname: Shendure
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Bamshad
mesh_terms: D000015:Abnormalities, Multiple / Q000175:diagnosis / Q000235:genetics*; D000483:Alleles; D004268:DNA-Binding Proteins / Q000235:genetics*; D005145:Face / Q000002:abnormalities; D023061:Gene Order; D005820:Genetic Testing; D005838:Genotype; D006402:Hematologic Diseases / Q000175:diagnosis / Q000235:genetics*; D006801:Humans; D009154:Mutation / Q000235:genetics*; D009363:Neoplasm Proteins / Q000235:genetics*; D010641:Phenotype; D011379:Prognosis; D015837:Vestibular Diseases / Q000175:diagnosis / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C120898:KMT2D protein, human; D009363:Neoplasm Proteins