1. How genetically heterogeneous is Kabuki syndrome?: MLL2 testing in 116 patients, review and analyses of mutation and phenotypic spectrum
- Author
-
Sixto García-Miñaur, Ratna Veeramachaneni, Susan Price, Nicola Ragge, Kay Metcalfe, Graeme C.M. Black, Christopher P. Bennett, William Reardon, Alex Magee, Soo Mi Park, Jill Clayton-Smith, Nicole Revencu, Bruce Castle, Christine Oley, Wayne W.K. Lam, Vivienne McConnell, Deirdre E. Donnelly, Deepthi De Silva, Andrew E. Fry, I. Karen Temple, Judith A. Goodship, Helen Kingston, Gunnar Houge, Fiona Stewart, Sally J. Davies, Frances Elmslie, John Tolmie, Sancha Bunstone, Harinder Gill, Emma Howard, Shehla Mohammed, Moira Blyth, Michael Parker, Emma Hobson, Dian Donnai, Michael Wright, Kate Chandler, Amanda L. Collins, Susann Schweiger, Katherine Lachlan, Alex Henderson, Richard Gibbons, Siren Berland, Audrey Smith, Sally Ann Lynch, Pradeep Vasudevan, Bronwyn Kerr, Richard Fisher, Meriel McEntagart, Jenny Morton, Siddharth Banka, Yanick J. Crow, UCL - SSS/IREC - Institut de recherche expérimentale et clinique, and UCL - (SLuc) Centre de génétique médicale UCL
- Subjects
Biology ,medicine.disease_cause ,Article ,Cohort Studies ,Genetic Heterogeneity ,Exon ,Genetics ,medicine ,Humans ,Missense mutation ,Abnormalities, Multiple ,Epigenetics ,Genetics (clinical) ,Mutation ,Genetic heterogeneity ,Cancer ,Sequence Analysis, DNA ,medicine.disease ,Hematologic Diseases ,Phenotype ,Neoplasm Proteins ,DNA-Binding Proteins ,Vestibular Diseases ,Face ,Female ,Kabuki syndrome - 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. © 2012 Macmillan Publishers Limited All rights reserved.
- Published
- 2011