Journal
NATURE GENETICS
Volume 42, Issue 9, Pages 790-U85Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/ng.646
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Funding
- Kabuki Syndrome Network
- US National Institutes of Health (NIH)-National Heart, Lung, and Blood Institute [5R01HL094976]
- NIH-National Human Genome Research Institute [5R21HG004749, 1RC2HG005608, 5RO1HG004316, T32HG00035]
- NIH-National Institute of Environmental Health Sciences [HHSN273200800010C]
- Ministry of Health, Labour and Welfare
- Japan Science and Technology Agency
- Society for the Promotion of Science
- Life Sciences Discovery Fund [2065508, 0905001]
- Washington Research Foundation
- NIH-National Institute of Child Health and Human Development [1R01HD048895]
- Agency for Science, Technology and Research, Singapore
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We demonstrate the successful application of exome sequencing(1-3) 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(4): 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.
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