Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome

Abstract

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.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Genomic structure and allelic spectrum of MLL2 mutations that cause Kabuki syndrome.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Choi, M. et al. Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. Proc. Natl. Acad. Sci. USA 106, 19096–19101 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Ng, S.B. et al. Exome sequencing identifies the cause of a Mendelian disorder. Nat. Genet. 42, 30–35 (2010).

    Article  CAS  PubMed  Google Scholar 

  3. Ng, S.B. et al. Targeted capture and massively parallel sequencing of 12 human exomes. Nature 461, 272–276 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. FitzGerald, K.T. & Diaz, M.O. MLL2: A new mammalian member of the trx/MLL family of genes. Genomics 59, 187–192 (1999).

    Article  CAS  PubMed  Google Scholar 

  5. Niikawa, N., Matsuura, N., Fukushima, Y., Ohsawa, T. & Kajii, T. Kabuki make-up syndrome: a syndrome of mental retardation, unusual facies, large and protruding ears, and postnatal growth deficiency. J. Pediatr. 99, 565–569 (1981).

    Article  CAS  PubMed  Google Scholar 

  6. Kuroki, Y., Suzuki, Y., Chyo, H., Hata, A. & Matsui, I. A new malformation syndrome of long palpebral fissures, large ears, depressed nasal tip, and skeletal anomalies associated with postnatal dwarfism and mental retardation. J. Pediatr. 99, 570–573 (1981).

    Article  CAS  PubMed  Google Scholar 

  7. Niikawa, N. et al. Kabuki make-up (Niikawa-Kuroki) syndrome: a study of 62 patients. Am. J. Med. Genet. 31, 565–589 (1988).

    Article  CAS  PubMed  Google Scholar 

  8. Courtens, W., Rassart, A., Stene, J.J. & Vamos, E. Further evidence for autosomal dominant inheritance and ectodermal abnormalities in Kabuki syndrome. Am. J. Med. Genet. 93, 244–249 (2000).

    Article  CAS  PubMed  Google Scholar 

  9. Cooper, G.M. et al. Distribution and intensity of constraint in mammalian genomic sequence. Genome Res. 15, 901–913 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Cooper, G.M. et al. Single-nucleotide evolutionary constraint scores highlight disease-causing mutations. Nat. Methods 7, 250–251 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Prasad, R. et al. Structure and expression pattern of human ALR, a novel gene with strong homology to ALL-1 involved in acute leukemia and to Drosophila trithorax. Oncogene 15, 549–560 (1997).

    Article  CAS  PubMed  Google Scholar 

  12. Issaeva, I. et al. Knockdown of ALR (MLL2) reveals ALR target genes and leads to alterations in cell adhesion and growth. Mol. Cell. Biol. 27, 1889–1903 (2007).

    Article  CAS  PubMed  Google Scholar 

  13. Glaser, S. et al. Multiple epigenetic maintenance factors implicated by the loss of Mll2 in mouse development. Development 133, 1423–1432 (2006).

    Article  CAS  PubMed  Google Scholar 

  14. Tonoki, H., Saitoh, S. & Kobayashi, K. Patient with del(12)(q12q13.12) manifesting abnormalities compatible with Noonan syndrome. Am. J. Med. Genet. 75, 416–418 (1998).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

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).

Author information

Authors and Affiliations

Authors

Contributions

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.

Corresponding authors

Correspondence to Michael J Bamshad or Jay Shendure.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–3 and Supplementary Tables 1–3 (PDF 335 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

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). https://doi.org/10.1038/ng.646

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ng.646

This article is cited by

Search

Quick links

Nature Briefing: Translational Research

Sign up for the Nature Briefing: Translational Research newsletter — top stories in biotechnology, drug discovery and pharma.

Get what matters in translational research, free to your inbox weekly. Sign up for Nature Briefing: Translational Research