Spectrum of <i>MLL2</i> (<i>ALR</i>) mutations in 110 cases of Kabuki syndrome

TLDR

Kabuki syndrome is a rare multiple malformation disorder with distinctive facial features, cardiac and skeletal anomalies, mild intellectual disability, and is predominantly autosomal dominant with most cases being simplex. The authors screened 110 Kabuki syndrome families to identify MLL2 mutations. MLL2 mutations were detected in 74% of families, mostly novel nonsense or frameshift variants, with 25 de novo and two transmitted in familial cases, and mutation‑positive patients had similar clinical features to mutation‑negative ones except for a higher frequency of renal anomalies, underscoring the phenotypic impact of MLL2 loss and guiding future gene discovery. © 2011 Wiley‑Liss, Inc.

Abstract

Abstract 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.