title: How genetically heterogeneous is Kabuki syndrome?: MLL2 testing in 116 patients, review and analyses of mutation and phenotypic spectrum.
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.
authors: Department of Genetic Medicine, St Mary's Hospital, Manchester Academic Health Sciences Centre (MAHSC), University of Manchester, Manchester, UK.
authors: Siddharth
authors: S
authors: Banka
authors: Ratna
authors: R
authors: Veeramachaneni
authors: William
authors: W
authors: Reardon
authors: Emma
authors: E
authors: Howard
authors: Sancha
authors: S
authors: Bunstone
authors: Nicola
authors: N
authors: Ragge
authors: Michael J
authors: MJ
authors: Parker
authors: Yanick J
authors: YJ
authors: Crow
authors: Bronwyn
authors: B
authors: Kerr
authors: Helen
authors: H
authors: Kingston
authors: Kay
authors: K
authors: Metcalfe
authors: Kate
authors: K
authors: Chandler
authors: Alex
authors: A
authors: Magee
authors: Fiona
authors: F
authors: Stewart
authors: Vivienne P M
authors: VP
authors: McConnell
authors: Deirdre E
authors: DE
authors: Donnelly
authors: Siren
authors: S
authors: Berland
authors: Gunnar
authors: G
authors: Houge
authors: Jenny E
authors: JE
authors: Morton
authors: Christine
authors: C
authors: Oley
authors: Nicole
authors: N
authors: Revencu
authors: Soo-Mi
authors: SM
authors: Park
authors: Sally J
authors: SJ
authors: Davies
authors: Andrew E
authors: AE
authors: Fry
authors: Sally Ann
authors: SA
authors: Lynch
authors: Harinder
authors: H
authors: Gill
authors: Susann
authors: S
authors: Schweiger
authors: Wayne W K
authors: WW
authors: Lam
authors: John
authors: J
authors: Tolmie
authors: Shehla N
authors: SN
authors: Mohammed
authors: Emma
authors: E
authors: Hobson
authors: Audrey
authors: A
authors: Smith
authors: Moira
authors: M
authors: Blyth
authors: Christopher
authors: C
authors: Bennett
authors: Pradeep C
authors: PC
authors: Vasudevan
authors: Sixto
authors: S
authors: García-Miñaúr
authors: Alex
authors: A
authors: Henderson
authors: Judith
authors: J
authors: Goodship
authors: Michael J
authors: MJ
authors: Wright
authors: Richard
authors: R
authors: Fisher
authors: Richard
authors: R
authors: Gibbons
authors: Susan M
authors: SM
authors: Price
authors: Deepthi
authors: D
authors: C de Silva
authors: I Karen
authors: IK
authors: Temple
authors: Amanda L
authors: AL
authors: Collins
authors: Katherine
authors: K
authors: Lachlan
authors: Frances
authors: F
authors: Elmslie
authors: Meriel
authors: M
authors: McEntagart
authors: Bruce
authors: B
authors: Castle
authors: Jill
authors: J
authors: Clayton-Smith
authors: Graeme C
authors: GC
authors: Black
authors: Dian
authors: D
authors: Donnai
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D015331:Cohort Studies; D004268:DNA-Binding Proteins / Q000235:genetics*; D005145:Face / Q000002:abnormalities; D005260:Female; D018740:Genetic Heterogeneity; D006402:Hematologic Diseases / Q000235:genetics*; D006801:Humans; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D010641:Phenotype; D017422:Sequence Analysis, DNA; D015837:Vestibular Diseases / Q000235:genetics*
chemical_list: D004268:DNA-Binding Proteins; C120898:KMT2D protein, human; D009363:Neoplasm Proteins