MLL2 Mutation Spectrum in 45 Patients with Kabuki Syndrome

Aimee D. C. Paulussen*, Alexander P. A. Stegmann, Marinus J. Blok, Demis Tserpelis, Crool Posma-Velter, Yvonne Detisch, Eric E. J. G. L. Smeets, Annemieke Wagemans, Jaap J. P. Schrander, Marie-Jose H. van den Boogaard, Jasper van der Smagt, Arie van Haeringen, Irene Stolte-Dijkstra, Wilhelmina S. Kerstjens-Frederikse, Grazia M. Mancini, Marja W. Wessels, Raoul C. M. Hennekam, Maaike Vreeburg, Joep Geraedts, Thomy de RavelJean-Pierre Fryns, Hubert J. Smeets, Koenraad Devriendt, Constance T. R. M. Schrander-Stumpel

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

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    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. (C) 2010 Wiley-Liss, Inc.

    Original languageEnglish
    Pages (from-to)E2018-E2025
    Number of pages8
    JournalHuman Mutation
    Volume32
    Issue number2
    DOIs
    Publication statusPublished - Feb-2011

    Keywords

    • Kabuki syndrome
    • KS
    • MLL2
    • histone methyl transferase
    • PROTEIN LYSINE METHYLTRANSFERASES
    • MAKE-UP-SYNDROME
    • MENTAL-RETARDATION
    • GROWTH
    • EARS
    • GENE

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