title: MLL2 mutation spectrum in 45 patients with Kabuki syndrome.
abstract: Kabuki Syndrome (KS) is a rare syndrome characterized by intellectual disability and multiple congenital abnormalities, in particular a distinct dysmorphic facial appearance. KS is caused by mutations in the MLL2 gene, encoding an H3K4 histone methyl transferase which acts as an epigenetic transcriptional activator during growth and development. Direct sequencing of all 54 exons of the MLL2 gene in 45 clinically well-defined KS patients identified 34 (75.6%) different mutations. One mutation has been described previously, all others are novel. Clinically, all KS patients were sporadic, and mutations were de novo for all 27 families for which both parents were available. We detected nonsense (n=11), frameshift (n=17), splice site (n=4) and missense (n=2) mutations, predicting a high frequency of absent or non-functional MLL2 protein. Interestingly, both missense mutations located in the C-terminal conserved functional domains of the protein. Phenotypically our study indicated a statistically significant difference in the presence of a distinct facial appearance (p=0.0143) and growth retardation (p=0.0040) when comparing KS patients with an MLL2 mutation compared to patients without a mutation. Our data double the number of MLL2 mutations in KS reported so far and widen the spectrum of MLL2 mutations and disease mechanisms in KS.
authors.affiliation: Department of Clinical Genetics, Maastricht UMC+, Maastricht, the Netherlands. aimee.paulussen@mumc.nl
authors.forename: Aimée D C
authors.initials: AD
authors.lastname: Paulussen
authors.forename: Alexander P A
authors.initials: AP
authors.lastname: Stegmann
authors.forename: Marinus J
authors.initials: MJ
authors.lastname: Blok
authors.forename: Demis
authors.initials: D
authors.lastname: Tserpelis
authors.forename: Crool
authors.initials: C
authors.lastname: Posma-Velter
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Detisch
authors.forename: Eric E J G L
authors.initials: EE
authors.lastname: Smeets
authors.forename: Annemieke
authors.initials: A
authors.lastname: Wagemans
authors.forename: Jaap J P
authors.initials: JJ
authors.lastname: Schrander
authors.forename: Marie-José H
authors.initials: MJ
authors.lastname: van den Boogaard
authors.forename: Jasper
authors.initials: J
authors.lastname: van der Smagt
authors.forename: Arie
authors.initials: A
authors.lastname: van Haeringen
authors.forename: Irene
authors.initials: I
authors.lastname: Stolte-Dijkstra
authors.forename: Wilhelmina S
authors.initials: WS
authors.lastname: Kerstjens-Frederikse
authors.forename: Grazia M
authors.initials: GM
authors.lastname: Mancini
authors.forename: Marja W
authors.initials: MW
authors.lastname: Wessels
authors.forename: Raoul C M
authors.initials: RC
authors.lastname: Hennekam
authors.forename: Maaike
authors.initials: M
authors.lastname: Vreeburg
authors.forename: Joep
authors.initials: J
authors.lastname: Geraedts
authors.forename: Thomy
authors.initials: T
authors.lastname: de Ravel
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Fryns
authors.forename: Hubert J
authors.initials: HJ
authors.lastname: Smeets
authors.forename: Koenraad
authors.initials: K
authors.lastname: Devriendt
authors.forename: Constance T R M
authors.initials: CT
authors.lastname: Schrander-Stumpel
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D005145:Face / Q000002:abnormalities; D005260:Female; D006402:Hematologic Diseases / Q000235:genetics; D006801:Humans; D008297:Male; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics*; D015837:Vestibular Diseases / Q000235:genetics
chemical_list: D004268:DNA-Binding Proteins; C120898:KMT2D protein, human; D009363:Neoplasm Proteins