Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome - PubMed (original) (raw)

doi: 10.1038/ng.646. Epub 2010 Aug 15.

Abigail W Bigham, Kati J Buckingham, Mark C Hannibal, Margaret J McMillin, Heidi I Gildersleeve, Anita E Beck, Holly K Tabor, Gregory M Cooper, Heather C Mefford, Choli Lee, Emily H Turner, Joshua D Smith, Mark J Rieder, Koh-Ichiro Yoshiura, Naomichi Matsumoto, Tohru Ohta, Norio Niikawa, Deborah A Nickerson, Michael J Bamshad, Jay Shendure

Affiliations

Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome

Sarah B Ng et al. Nat Genet. 2010 Sep.

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.

PubMed Disclaimer

Figures

Figure 1

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

MLL2 is composed of 54 exons that encode untranslated regions (orange) and protein coding sequence (blue) including 7 PHD fingers (yellow), FYRN (green), FYRC (green), and a SET domain (red). Arrows indicate the locations of 32 different mutations found in 53 families with Kabuki syndrome including: 20 nonsense, 7 indels, and 5 amino acid substitutions. Asterisks indicate mutations that were confirmed to be de novo and crosses indicate cases for which parental DNA was unavailable.

Comment in

Similar articles

Cited by

References

    1. Choi M, et al. Genetic diagnosis by whole exome capture and massively parallel DNA sequencing. Proc Natl Acad Sci U S A. 2009;106:19096–19101. - PMC - PubMed
    1. Ng SB, et al. Exome sequencing identifies the cause of a mendelian disorder. Nat Genet. 2010;42:30–35. - PMC - PubMed
    1. Ng SB, et al. Targeted capture and massively parallel sequencing of 12 human exomes. Nature. 2009;461:272–276. - PMC - PubMed
    1. FitzGerald KT, Diaz MO. MLL2: A new mammalian member of the trx/MLL family of genes. Genomics. 1999;59:187–192. - PubMed
    1. 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. 1981;99:565–569. - PubMed

Publication types

MeSH terms

Substances

Grants and funding

LinkOut - more resources