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Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome


We demonstrate the successful application of exome sequencing1,2,3 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 methyltransferase4: 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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Figure 1: Genomic structure and allelic spectrum of MLL2 mutations that cause Kabuki syndrome.

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We thank the families for their participation and the Kabuki Syndrome Network for their support. We thank J. Allanson, J. Carey and M. Golabi for referral of cases and M. Emond for helpful discussion. We thank the 1000 Genomes Project for early data release that proved useful for filtering out common variants. Our work was supported in part by grants from the US National Institutes of Health (NIH)–National Heart, Lung, and Blood Institute (5R01HL094976 to D.A.N. and J.S.), the NIH–National Human Genome Research Institute (5R21HG004749 to J.S., 1RC2HG005608 to M.J.B., D.A.N. and J.S.; and 5RO1HG004316 to H.K.T.), NIH–National Institute of Environmental Health Sciences (HHSN273200800010C to D.N. and M.J.R.), Ministry of Health, Labour and Welfare (K.Y., N.M., T.O. and N.N.), Japan Science and Technology Agency (N.M.), Society for the Promotion of Science (N.M.), the Life Sciences Discovery Fund (2065508 and 0905001), the Washington Research Foundation and the NIH–National Institute of Child Health and Human Development (1R01HD048895 to M.J.B.). S.B.N. is supported by the Agency for Science, Technology and Research, Singapore. A.W.B. is supported by a training fellowship from the NIH–National Human Genome Research Institute (T32HG00035).

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The project was conceived and the experiments were planned by M.J.B., D.A.N. and J.S. The review of phenotypes and the sample collection were performed by M.J.B., M.C.H., M.J.M., K.Y., N.M., T.O. and N.N. Experiments were performed by S.B.N., K.J.B., A.E.B., C.L., H.C.M., J.D.S., M.J.R., E.H.T. and H.I.G. Ethical consultation was provided by H.K.T. Data analysis was performed by A.W.B., M.J.B., K.J.B., G.M.C., S.B.N. and J.S. The manuscript was written by M.J.B., S.B.N. and J.S. All aspects of the study were supervised by M.J.B. and J.S.

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Correspondence to Michael J Bamshad or Jay Shendure.

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The authors declare no competing financial interests.

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Ng, S., Bigham, A., Buckingham, K. et al. Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome. Nat Genet 42, 790–793 (2010).

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