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

Banka, Siddharth, Veeramachaneni, Ratna, Reardon, William, Howard, Emma, Bunstone, Sancha, Ragge, Nicola, Parker, Michael J, Crow, Yanick J, Kerr, Bronwyn, Kingston, Helen, Metcalfe, Kay, Chandler, Kate, Magee, Alex, Stewart, Fiona, McConnell, Vivienne P M, Donnelly, Deirdre E, Berland, Siren, Houge, Gunnar, Morton, Jenny E, Oley, Christine, Revencu, Nicole, Park, Soo-Mi, Davies, Sally J, Fry, Andrew E, Lynch, Sally Ann, Gill, Harinder, Schweiger, Susann, Lam, Wayne W K, Tolmie, John, Mohammed, Shehla N, Hobson, Emma, Smith, Audrey, Blyth, Moira, Bennett, Christopher, Vasudevan, Pradeep C, García-Miñaúr, Sixto, Henderson, Alex, Goodship, Judith, Wright, Michael J, Fisher, Richard, Gibbons, Richard, Price, Susan M, C de Silva, Deepthi, Temple, I Karen, Collins, Amanda L, Lachlan, Katherine, Elmslie, Frances, McEntagart, Meriel, Castle, Bruce, Clayton-Smith, Jill, Black, Graeme C and Donnai, Dian (2012) How genetically heterogeneous is Kabuki syndrome?: MLL2 testing in 116 patients, review and analyses of mutation and phenotypic spectrum European Journal of Human Genetics, 20, (4), pp. 381-388. (doi:10.1038/ejhg.2011.220). (PMID:22126750).

Record type: Article


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.

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e-pub ahead of print date: 30 November 2011
Published date: April 2012
Organisations: Human Development & Health


Local EPrints ID: 205421
ISSN: 1018-4813
PURE UUID: eeb65b79-f213-4326-810e-96d49203848a

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Date deposited: 07 Dec 2011 14:46
Last modified: 18 Jul 2017 11:04

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

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