Spectrum of MLL2 (ALR) mutations in 110 cases of Kabuki syndrome

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...

Full description

Saved in:

Bibliographic Details
Published in:	American journal of medical genetics. Part A Vol. 155A; no. 7; pp. 1511 - 1516
Main Authors:	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.
Format:	Journal Article
Language:	English
Published:	Hoboken Wiley Subscription Services, Inc., A Wiley Company 01-07-2011 Wiley-Liss
Subjects:	Abnormalities, Multiple - diagnosis Abnormalities, Multiple - genetics Alleles ALR Biological and medical sciences Chromatin Congenital defects DNA DNA-Binding Proteins - genetics epigenetics Face - abnormalities Frameshift mutation Gene Order Genetic Testing Genotype haploinsufficiency Heart Hematologic Diseases - diagnosis Hematologic Diseases - genetics Hereditary diseases histone methyltransferase Humans Kabuki syndrome Kidney Medical genetics Medical sciences Mental retardation MLL2 Mutation - genetics Neoplasm Proteins - genetics Phenotype Prognosis Trithorax group histone methyltransferase Vestibular Diseases - diagnosis Vestibular Diseases - genetics MLL2 Enzyme Transferases ALR Kabuki make-up syndrome Spectrum Case study Methyltransferases Malformation Kabuki syndrome Trithorax group histone methyltransferase Mutation Complex syndrome Histone
Online Access:	Get full text
Tags:	Add Tag No Tags, Be the first to tag this record!

Description
Summary:	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.
Bibliography:	Life Sciences Discovery Fund - No. 2065508; No. 0905001 National Institutes of Health/National Institute of Child Health and Human Development - No. 1R01HD048895; No. 5K23HD057331 National Institutes of Health/National Heart Lung and Blood Institute - No. 5R01HL094976 National Institutes of Health/National Human Genome Research Institute - No. 5R21HG004749; No. 1RC2HG005608; No. 5RO1HG004316; No. T32HG00035 Ministry of Health, Labour and Welfare of Japan Mark C. Hannibal, Kati J. Buckingham, and Sarah B. Ng contributed equally to this work. ArticleID:AJMG34074 National Institute of Heath/National Institute of Environmental Health Sciences - No. HHSN273200800010C How to Cite this Article: Hannibal MC, Buckingham KJ, Ng SB, Ming JE, Beck AE, McMillin MJ, Gildersleeve HI, Bigham AW, Tabor HK, Mefford HC, Cook J, Yoshiura K-i, Matsumoto T, Matsumoto N, Miyake N, Tonoki H, Naritomi K, Kaname T, Nagai T, Ohashi H, Kurosawa K, Hou J-W, Ohta T, Liang D, Sudo A, Morris CA, Banka S, Black GC, Clayton-Smith J, Nickerson DA, Zackai EH, Shaikh TH, Donnai D, Niikawa N, Shendure J, Bamshad MJ. 2011. Spectrum of MLL2 (ALR) mutations in 110 cases of Kabuki syndrome. Am J Med Genet Part A 155:1511-1516. National Institute of Neurological Disorders and Stroke - No. RO1NS35102 Society for the Promotion of Science Washington Research Foundation istex:D99ACE8B7D09417FCB31978CF19D497ABDBEE0CC NIHR Manchester Biomedical Research Centre Japan Science and Technology Agency ark:/67375/WNG-5TRC2JD6-Q mutations in 110 cases of Kabuki syndrome. Am J Med Genet Part A 155:1511–1516. ( MLL2 How to Cite this Article: Hannibal MC, Buckingham KJ, Ng SB, Ming JE, Beck AE, McMillin MJ, Gildersleeve HI, Bigham AW, Tabor HK, Mefford HC, Cook J, Yoshiura K‐i, Matsumoto T, Matsumoto N, Miyake N, Tonoki H, Naritomi K, Kaname T, Nagai T, Ohashi H, Kurosawa K, Hou J‐W, Ohta T, Liang D, Sudo A, Morris CA, Banka S, Black GC, Clayton‐Smith J, Nickerson DA, Zackai EH, Shaikh TH, Donnai D, Niikawa N, Shendure J, Bamshad MJ. 2011. Spectrum of ALR ObjectType-Article-2 SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 23 ObjectType-Article-1 ObjectType-Feature-2 These authors contributed equally to this work.
ISSN:	1552-4825 1552-4833 1552-4833
DOI:	10.1002/ajmg.a.34074