title: Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome.
abstract: We demonstrate the successful application of exome sequencing to discover a gene for an autosomal dominant disorder, Kabuki syndrome (OMIM%147920). We subjected the exomes of ten unrelated probands to massively parallel sequencing. After filtering against existing SNP databases, there was no compelling candidate gene containing previously unknown variants in all affected individuals. Less stringent filtering criteria allowed for the presence of modest genetic heterogeneity or missing data but also identified multiple candidate genes. However, genotypic and phenotypic stratification highlighted MLL2, which encodes a Trithorax-group histone methyltransferase: seven probands had newly identified nonsense or frameshift mutations in this gene. Follow-up Sanger sequencing detected MLL2 mutations in two of the three remaining individuals with Kabuki syndrome (cases) and in 26 of 43 additional cases. In families where parental DNA was available, the mutation was confirmed to be de novo (n = 12) or transmitted (n = 2) in concordance with phenotype. Our results strongly suggest that mutations in MLL2 are a major cause of Kabuki syndrome.
authors: Department of Genome Sciences, University of Washington, Seattle, Washington, USA.
authors: Sarah B
authors: SB
authors: Ng
authors: Abigail W
authors: AW
authors: Bigham
authors: Kati J
authors: KJ
authors: Buckingham
authors: Mark C
authors: MC
authors: Hannibal
authors: Margaret J
authors: MJ
authors: McMillin
authors: Heidi I
authors: HI
authors: Gildersleeve
authors: Anita E
authors: AE
authors: Beck
authors: Holly K
authors: HK
authors: Tabor
authors: Gregory M
authors: GM
authors: Cooper
authors: Heather C
authors: HC
authors: Mefford
authors: Choli
authors: C
authors: Lee
authors: Emily H
authors: EH
authors: Turner
authors: Joshua D
authors: JD
authors: Smith
authors: Mark J
authors: MJ
authors: Rieder
authors: Koh-Ichiro
authors: K
authors: Yoshiura
authors: Naomichi
authors: N
authors: Matsumoto
authors: Tohru
authors: T
authors: Ohta
authors: Norio
authors: N
authors: Niikawa
authors: Deborah A
authors: DA
authors: Nickerson
authors: Michael J
authors: MJ
authors: Bamshad
authors: Jay
authors: J
authors: Shendure
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005787:Gene Frequency; D008040:Genetic Linkage; D020022:Genetic Predisposition to Disease; D006801:Humans; D009154:Mutation / Q000502:physiology; D009363:Neoplasm Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D017422:Sequence Analysis, DNA / Q000379:methods*; D013577:Syndrome; D054928:Validation Studies as Topic
chemical_list: D004268:DNA-Binding Proteins; C120898:KMT2D protein, human; D009363:Neoplasm Proteins