How genetically heterogeneous is Kabuki syndrome? MLL2 testing in 116 patients, review and analyses of mutation and phenotypic spectrum

Siddharth Banka, Ratna Veeramachaneni, William Reardon, Emma Howard, Sancha Bunstone, Nicola Ragge, Michael J. Parker, Yanick J. Crow, Bronwyn Kerr, Helen Kingston, Kay Metcalfe, Kate Chandler, Alex Magee, Fiona Stewart, Vivienne P. M. McConnell, Deirdre E. Donnelly, Siren Berland, Gunnar Houge, Jenny E. Morton, Christine OleyNicole Revencu, Soo-Mi Park, Sally J. Davies, Andrew E. Fry, Sally Ann Lynch, Harinder Gill, Susann Schweiger, Wayne W. K. Lam, John Tolmie, Shehla N. Mohammed, Emma Hobson, Audrey Smith, Moira Blyth, Christopher Bennett, Pradeep C. Vasudevan, Sixto Garcia-Minaur, Alex Henderson, Judith Goodship, Michael J. Wright, Richard Fisher, Richard Gibbons, Susan M. Price, Deepthi C. de Silva, I. Karen Temple, Amanda L. Collins, Katherine Lachlan, Frances Elmslie, Meriel McEntagart, Bruce Castle, Jill Clayton-Smith, Graeme C. Black, Dian Donnai

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    134 Citations (Scopus)


    MLL2 mutations are detected in 55 to 80% of patients with Kabuki syndrome (KS). In 20 to 45% patients with KS, the genetic basis remains unknown, suggesting possible genetic heterogeneity. Here, we present the largest yet reported cohort of 116 patients with KS. We identified MLL2 variants in 74 patients, of which 47 are novel and a majority are truncating. We show that pathogenic missense mutations were commonly located in exon 48. We undertook a systematic facial KS morphology study of patients with KS at our regional dysmorphology meeting. Our data suggest that nearly all patients with typical KS facial features have pathogenic MLL2 mutations, although KS can be phenotypically variable. Furthermore, we show that MLL2 mutation-positive KS patients are more likely to have feeding problems, kidney anomalies, early breast bud development, joint dislocations and palatal malformations in comparison with MLL2 mutation-negative patients. Our work expands the mutation spectrum of MLL2 that may help in better understanding of this molecule, which is important in gene expression, epigenetic control of active chromatin states, embryonic development and cancer. Our analyses of the phenotype indicates that MLL2 mutation-positive and -negative patients differ systematically, and genetic heterogeneity of KS is not as extensive as previously suggested. Moreover, phenotypic variability of KS suggests that MLL2 testing should be considered even in atypical patients. European Journal of Human Genetics (2012) 20, 381-388; doi: 10.1038/ejhg.2011.220; published online 30 November 2011

    Original languageEnglish
    Pages (from-to)381-388
    Number of pages8
    JournalEuropean Journal of Human Genetics
    Issue number4
    Publication statusPublished - Apr 2012


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