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

Lookup NU author(s): Dr Sally Lynch, Professor Judith Goodship, Dr Michael Wright, Dr Richard Fisher

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Abstract

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


Publication metadata

Author(s): Banka S, Veeramachaneni R, Reardon W, Howard E, Bunstone S, Ragge N, Parker MJ, Crow YJ, Kerr B, Kingston H, Metcalfe K, Chandler K, Magee A, Stewart F, McConnell VPM, Donnelly DE, Berland S, Houge G, Morton JE, Oley C, Revencu N, Park SM, Davies SJ, Fry AE, Lynch SA, Gill H, Schweiger S, Lam WWK, Tolmie J, Mohammed SN, Hobson E, Smith A, Blyth M, Bennett C, Vasudevan PC, Garcia-Minaur S, Henderson A, Goodship J, Wright MJ, Fisher R, Gibbons R, Price SM, de Silva DC, Temple IK, Collins AL, Lachlan K, Elmslie F, McEntagart M, Castle B, Clayton-Smith J, Black GC, Donnai D

Publication type: Article

Publication status: Published

Journal: European Journal of Human Genetics

Year: 2012

Volume: 20

Issue: 4

Pages: 381-388

Print publication date: 01/04/2012

ISSN (print): 1018-4813

ISSN (electronic): 1476-5438

Publisher: Nature Publishing Group

URL: http://dx.doi.org/10.1038/ejhg.2011.220

DOI: 10.1038/ejhg.2011.220


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