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Spectrum of MLL2 ( ALR ) mutations in 110 cases of Kabuki syndrome
Author(s) -
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 Kohichiro,
Matsumoto Tadashi,
Matsumoto Naomichi,
Miyake Noriko,
Tonoki Hidefumi,
Naritomi Kenji,
Kaname Tadashi,
Nagai Toshiro,
Ohashi Hirofumi,
Kurosawa Kenji,
Hou JiaWoei,
Ohta Tohru,
Liang Deshung,
Sudo Akira,
Morris Colleen A.,
Banka Siddharth,
Black Graeme C.,
ClaytonSmith Jill,
Nickerson Deborah A.,
Zackai Elaine H.,
Shaikh Tamim H.,
Donnai Dian,
Niikawa Norio,
Shendure Jay,
Bamshad Michael J.
Publication year - 2011
Publication title -
american journal of medical genetics part a
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.064
H-Index - 112
eISSN - 1552-4833
pISSN - 1552-4825
DOI - 10.1002/ajmg.a.34074
Subject(s) - kabuki syndrome , haploinsufficiency , frameshift mutation , genetics , mutation , nonsense mutation , biology , gene , phenotype , missense mutation
Kabuki syndrome is a rare, multiple malformation disorder characterized by a distinctive facial appearance, cardiac anomalies, skeletal abnormalities, and mild to moderate intellectual disability. Simplex cases make up the vast majority of the reported cases with Kabuki syndrome, but parent‐to‐child transmission in more than a half‐dozen instances indicates that it is an autosomal dominant disorder. We recently reported that Kabuki syndrome is caused by mutations in MLL2 , a gene that encodes a Trithorax‐group histone methyltransferase, a protein important in the epigenetic control of active chromatin states. Here, we report on the screening of 110 families with Kabuki syndrome. MLL2 mutations were found in 81/110 (74%) of families. In simplex cases for which DNA was available from both parents, 25 mutations were confirmed to be de novo, while a transmitted MLL2 mutation was found in two of three familial cases. The majority of variants found to cause Kabuki syndrome were novel nonsense or frameshift mutations that are predicted to result in haploinsufficiency. The clinical characteristics of MLL2 mutation‐positive cases did not differ significantly from MLL2 mutation‐negative cases with the exception that renal anomalies were more common in MLL2 mutation‐positive cases. These results are important for understanding the phenotypic consequences of MLL2 mutations for individuals and their families as well as for providing a basis for the identification of additional genes for Kabuki syndrome. © 2011 Wiley‐Liss, Inc.