Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome.

TitleExome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome.
Publication TypeJournal Article
Year of Publication2010
AuthorsNg SB, Bigham AW, Buckingham KJ, Hannibal MC, McMillin MJ, Gildersleeve HI, Beck AE, Tabor HK, Cooper GM, Mefford HC, Lee C, Turner EH, Smith JD, Rieder MJ, Yoshiura K-ichiro, Matsumoto N, Ohta T, Niikawa N, Nickerson DA, Bamshad MJ, Shendure J
JournalNature genetics
Date Published2010 Sep
KeywordsAbnormalities, Multiple, DNA-Binding Proteins, Gene Frequency, Genetic Linkage, Genetic Predisposition to Disease, Humans, Mutation, Neoplasm Proteins, Polymorphism, Single Nucleotide, Sequence Analysis, DNA, Syndrome, Validation Studies as Topic

We demonstrate the successful application of exomei sequencing to discover a genei 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 genesi. However, genotypic and phenotypic stratification highlighted MLL2, which encodes a Trithorax-group histonei methyltransferasei: 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 DNAi was available, the mutation was confirmed to be de novo (n = 12) or transmitted (n = 2) in concordance with phenotypei. Our results strongly suggest that mutations in MLL2 are a major cause of Kabuki syndrome.

Alternate JournalNat. Genet.
Citation Key411