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MLL2 mutation spectrum in 45 patients with Kabuki syndrome
Author(s) -
Paulussen Aimée D. C.,
Stegmann Alexander P. A.,
Blok Marinus J.,
Tserpelis Demis,
PosmaVelter Crool,
Detisch Yvonne,
Smeets Eric E. J. G. L.,
Wagemans Annemieke,
Schrander Jaap J. P.,
van den Boogaard MarieJosé H.,
van der Smagt Jasper,
van Haeringen Arie,
StolteDijkstra Irene,
KerstjensFrederikse Wilhelmina S.,
Mancini Grazia M.,
Wessels Marja W.,
Hennekam Raoul C. M.,
Vreeburg Maaike,
Geraedts Joep,
de Ravel Thomy,
Fryns JeanPierre,
Smeets Hubert J.,
Devriendt Koenraad,
SchranderStumpel Constance T. R. M.
Publication year - 2011
Publication title -
human mutation
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.981
H-Index - 162
eISSN - 1098-1004
pISSN - 1059-7794
DOI - 10.1002/humu.21416
Subject(s) - frameshift mutation , biology , missense mutation , genetics , kabuki syndrome , exon , mutation , nonsense mutation , gene , epigenetics
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. © 2010 Wiley‐Liss, Inc.