Recently, pathogenic variants in the MLL2 gene were identified as the most common cause of Kabuki (Niikawa-Kuroki) syndrome (MIM#147920). To further elucidate the genotype-phenotype correlation, we studied a large cohort of 86 clinically defined patients with Kabuki syndrome (KS) for mutations in MLL2. All patients were assessed using a standardized phenotype list and all were scored using a newly developed clinical score list for KS (MLL2-Kabuki score 0-10). Sequencing of the full coding region and intron-exon boundaries of MLL2 identified a total of 45 likely pathogenic mutations (52%): 31 nonsense, 10 missense and four splice-site mutations, 34 of which were novel. In five additional patients, novel, i.e. non-dbSNP132 variants of clinically unknown relevance, were identified. Patients with likely pathogenic nonsense or missense MLL2 mutations were usually more severely affected (median 'MLL2-Kabuki score' of 6) as compared to the patients without MLL2 mutations (median 'MLL2-Kabuki score' of 5), a significant difference (p < 0.0014). Several typical facial features such as large dysplastic ears, arched eyebrows with sparse lateral third, blue sclerae, a flat nasal tip with a broad nasal root, and a thin upper and a full lower lip were observed more often in mutation positive patients.
Ng Sarah B, Bigham Abigail W, Buckingham Kati J, Hannibal Mark C, McMillin Margaret J, Gildersleeve Heidi I, Beck Anita E, Tabor Holly K, Cooper Gregory M, Mefford Heather C, Lee Choli, Turner Emily H, Smith Joshua D, Rieder Mark J, Yoshiura Koh-ichiro, Matsumoto Naomichi, Ohta Tohru, Niikawa Norio, Nickerson Deborah A, Bamshad Michael J, Shendure Jay, Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome, 10.1038/ng.646
Banka Siddharth, Veeramachaneni Ratna, Reardon William, Howard Emma, Bunstone Sancha, Ragge Nicola, Parker Michael J, Crow Yanick J, Kerr Bronwyn, Kingston Helen, Metcalfe Kay, Chandler Kate, Magee Alex, Stewart Fiona, McConnell Vivienne P M, Donnelly Deirdre E, Berland Siren, Houge Gunnar, Morton Jenny E, Oley Christine, Revencu Nicole, Park Soo-Mi, Davies Sally J, Fry Andrew E, Lynch Sally Ann, Gill Harinder, Schweiger Susann, Lam Wayne W K, Tolmie John, Mohammed Shehla N, Hobson Emma, Smith Audrey, Blyth Moira, Bennett Christopher, Vasudevan Pradeep C, García-Miñaúr Sixto, Henderson Alex, Goodship Judith, Wright Michael J, Fisher Richard, Gibbons Richard, Price Susan M, C de Silva Deepthi, Temple I Karen, Collins Amanda L, Lachlan Katherine, Elmslie Frances, McEntagart Meriel, Castle Bruce, Clayton-Smith Jill, Black Graeme C, Donnai Dian, How genetically heterogeneous is Kabuki syndrome?: MLL2 testing in 116 patients, review and analyses of mutation and phenotypic spectrum, 10.1038/ejhg.2011.220
Hannibal Mark C., Buckingham Kati J., Ng Sarah B., Ming Jeffrey E., Beck Anita E., McMillin Margaret J., Gildersleeve Heidi I., Bigham Abigail W., Tabor Holly K., Mefford Heather C., Cook Joseph, Yoshiura Koh-ichiro, Matsumoto Tadashi, Matsumoto Naomichi, Miyake Noriko, Tonoki Hidefumi, Naritomi Kenji, Kaname Tadashi, Nagai Toshiro, Ohashi Hirofumi, Kurosawa Kenji, Hou Jia-Woei, Ohta Tohru, Liang Deshung, Sudo Akira, Morris Colleen A., Banka Siddharth, Black Graeme C., Clayton-Smith Jill, Nickerson Deborah A., Zackai Elaine H., Shaikh Tamim H., Donnai Dian, Niikawa Norio, Shendure Jay, Bamshad Michael J., Spectrum of MLL2 (ALR) mutations in 110 cases of Kabuki syndrome, 10.1002/ajmg.a.34074
Li Yun, Bögershausen Nina, Alanay Yasemin, Simsek Kiper Pelin Özlem, Plume Nadine, Keupp Katharina, Pohl Esther, Pawlik Barbara, Rachwalski Martin, Milz Esther, Thoenes Michaela, Albrecht Beate, Prott Eva-Christina, Lehmkühler Margret, Demuth Stephanie, Utine Gülen Eda, Boduroglu Koray, Frankenbusch Katja, Borck Guntram, Gillessen-Kaesbach Gabriele, Yigit Gökhan, Wieczorek Dagmar, Wollnik Bernd, A mutation screen in patients with Kabuki syndrome, 10.1007/s00439-011-1004-y
Micale Lucia, Augello Bartolomeo, Fusco Carmela, Selicorni Angelo, Loviglio Maria N, Silengo Margherita, Reymond Alexandre, Gumiero Barbara, Zucchetti Federica, D'Addetta Ester V, Belligni Elga, Calcagnì Alessia, Digilio Maria C, Dallapiccola Bruno, Faravelli Francesca, Forzano Francesca, Accadia Maria, Bonfante Aldo, Clementi Maurizio, Daolio Cecilia, Douzgou Sofia, Ferrari Paola, Fischetto Rita, Garavelli Livia, Lapi Elisabetta, Mattina Teresa, Melis Daniela, Patricelli Maria G, Priolo Manuela, Prontera Paolo, Renieri Alessandra, Mencarelli Maria A, Scarano Gioacchino, Monica Matteo, Toschi Benedetta, Turolla Licia, Vancini Alessandra, Zatterale Adriana, Gabrielli Orazio, Zelante Leopoldo, Merla Giuseppe, Mutation spectrum of MLL2 in a cohort of kabuki syndrome patients, 10.1186/1750-1172-6-38
Paulussen Aimée D. C., Stegmann Alexander P. A., Blok Marinus J., Tserpelis Demis, Posma-Velter Crool, Detisch Yvonne, Smeets Eric E. J. G. L., Wagemans Annemieke, Schrander Jaap J. P., van den Boogaard Marie-José H., van der Smagt Jasper, van Haeringen Arie, Stolte-Dijkstra Irene, Kerstjens-Frederikse Wilhelmina S., Mancini Grazia M., Wessels Marja W., Hennekam Raoul C. M., Vreeburg Maaike, Geraedts Joep, de Ravel Thomy, Fryns Jean-Pierre, Smeets Hubert J., Devriendt Koenraad, Schrander-Stumpel Constance T. R. M., MLL2 mutation spectrum in 45 patients with Kabuki syndrome, 10.1002/humu.21416
FitzGerald Kevin T., Diaz Manuel O., MLL2: A New Mammalian Member of the trx/MLL Family of Genes, 10.1006/geno.1999.5860
Douglas Jenny, Hanks Sandra, Temple I. Karen, Davies Sally, Murray Alexandra, Upadhyaya Meena, Tomkins Susan, Hughes Helen E., Trevor Cole R.P., Rahman Nazneen, NSD1 Mutations Are the Major Cause of Sotos Syndrome and Occur in Some Cases of Weaver Syndrome but Are Rare in Other Overgrowth Phenotypes, 10.1086/345647
Tatton-Brown Katrina, Hanks Sandra, Ruark Elise, Zachariou Anna, Duarte Silvana Del Vecchio, Ramsay Emma, Snape Katie, Murray Anne, Perdeaux Elizabeth R., Seal Sheila, Loveday Chey, Banka Siddharth, Clericuzio Carol, Flinter Frances, Magee Alex, McConnell Vivienne, Patton Michael, Raith Wolfgang, Rankin Julia, Splitt Miranda, Strenger Volker, Taylor Clare, Wheeler Patricia, Temple I. Karen, Cole Trevor, Douglas Jenny, Rahman Nazneen, Germline mutations in the oncogene EZH2 cause Weaver syndrome and increased human height, 10.18632/oncotarget.385
Gibson William T., Hood Rebecca L., Zhan Shing Hei, Bulman Dennis E., Fejes Anthony P., Moore Richard, Mungall Andrew J., Eydoux Patrice, Babul-Hirji Riyana, An Jianghong, Marra Marco A., Chitayat David, Boycott Kym M., Weaver David D., Jones Steven J.M., Mutations in EZH2 Cause Weaver Syndrome, 10.1016/j.ajhg.2011.11.018
Kleefstra T, Disruption of the gene Euchromatin Histone Methyl Transferase1 (Eu-HMTase1) is associated with the 9q34 subtelomeric deletion syndrome, 10.1136/jmg.2004.028464
Hoischen Alexander, van Bon Bregje W M, Gilissen Christian, Arts Peer, van Lier Bart, Steehouwer Marloes, de Vries Petra, de Reuver Rick, Wieskamp Nienke, Mortier Geert, Devriendt Koen, Amorim Marta Z, Revencu Nicole, Kidd Alexa, Barbosa Mafalda, Turner Anne, Smith Janine, Oley Christina, Henderson Alex, Hayes Ian M, Thompson Elizabeth M, Brunner Han G, de Vries Bert B A, Veltman Joris A, De novo mutations of SETBP1 cause Schinzel-Giedion syndrome, 10.1038/ng.581
Klein Christopher J, Botuyan Maria-Victoria, Wu Yanhong, Ward Christopher J, Nicholson Garth A, Hammans Simon, Hojo Kaori, Yamanishi Hiromitch, Karpf Adam R, Wallace Douglas C, Simon Mariella, Lander Cecilie, Boardman Lisa A, Cunningham Julie M, Smith Glenn E, Litchy William J, Boes Benjamin, Atkinson Elizabeth J, Middha Sumit, B Dyck P James, Parisi Joseph E, Mer Georges, Smith David I, Dyck Peter J, Mutations in DNMT1 cause hereditary sensory neuropathy with dementia and hearing loss, 10.1038/ng.830
Vicent G. P., Nacht A. S., Font-Mateu J., Castellano G., Gaveglia L., Ballare C., Beato M., Four enzymes cooperate to displace histone H1 during the first minute of hormonal gene activation, 10.1101/gad.621811
Mo Rigen, Rao Sambasiva M., Zhu Yi-Jun, Identification of the MLL2 Complex as a Coactivator for Estrogen Receptor α, 10.1074/jbc.m513245200
Demers Celina, Chaturvedi Chandra-Prakash, Ranish Jeffrey A., Juban Gaetan, Lai Patrick, Morle Francois, Aebersold Ruedi, Dilworth F. Jeffrey, Groudine Mark, Brand Marjorie, Activator-Mediated Recruitment of the MLL2 Methyltransferase Complex to the β-Globin Locus, 10.1016/j.molcel.2007.06.022
Kim Dae-Hwan, Lee Jeongkyung, Lee Bora, Lee Jae W., ASCOM Controls Farnesoid X Receptor Transactivation through Its Associated Histone H3 Lysine 4 Methyltransferase Activity, 10.1210/me.2009-0099
Kumar Prateek, Henikoff Steven, Ng Pauline C, Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm, 10.1038/nprot.2009.86
Tavtigian S V, Comprehensive statistical study of 452 BRCA1 missense substitutions with classification of eight recurrent substitutions as neutral, 10.1136/jmg.2005.033878
Li B., Krishnan V. G., Mort M. E., Xin F., Kamati K. K., Cooper D. N., Mooney S. D., Radivojac P., Automated inference of molecular mechanisms of disease from amino acid substitutions, 10.1093/bioinformatics/btp528
Liu Libin, Ho Yee-Kin, Yau Stephen, Prediction of Primate Splice Site Using Inhomogeneous Markov Chain and Neural Network, 10.1089/dna.2007.0583
Hebsgaard S., Splice site prediction in Arabidopsis thaliana pre-mRNA by combining local and global sequence information, 10.1093/nar/24.17.3439
Desmet François-Olivier, Hamroun Dalil, Lalande Marine, Collod-Béroud Gwenaëlle, Claustres Mireille, Béroud Christophe, Human Splicing Finder: an online bioinformatics tool to predict splicing signals, 10.1093/nar/gkp215
Lederer Damien, Grisart Bernard, Digilio Maria Cristina, Benoit Valérie, Crespin Marianne, Ghariani Sophie Claire, Maystadt Isabelle, Dallapiccola Bruno, Verellen-Dumoulin Christine, Deletion of KDM6A, a Histone Demethylase Interacting with MLL2, in Three Patients with Kabuki Syndrome, 10.1016/j.ajhg.2011.11.021
Banka, Clin Genet (2012)
Bibliographic reference
Makrythanasis, P ; van Bon, Bw ; Steehouwer, M ; Rodríguez-Santiago, B ; Simpson, M ; et. al. MLL2 mutation detection in 86 patients with Kabuki syndrome: a genotype-phenotype study. In: Clinical Genetics : an international journal of genetics and molecular medicine, Vol. 84, no. 6, p. 539-545 (2013)
Hoischen, A
