We demonstrate the successful application of exome sequencing1–3 to discover a gene for an autosomal dominant disorder, Kabuki syndrome (OMIM %147920). The exomes of ten unrelated probands were subjected to massively parallel sequencing. After filtering against SNP databases, there was no compelling candidate gene containing novel variants in all affected individuals. Less stringent filtering criteria permitted modest genetic heterogeneity or missing data, but identified multiple candidate genes. However, genotypic and phenotypic stratification highlighted MLL2, a Trithorax-group histone methyltransferase4, in which seven probands had novel nonsense or frameshift mutations. Follow-up Sanger sequencing detected MLL2 mutations in two of the three remaining cases, and in 26 of 43 additional cases. In families where parental DNA was available, the mutation was confirmed to be de novo (n = 12) or transmitted (n = 2) in concordance with phenotype. Our results strongly suggest that mutations in MLL2 are a major cause 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 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.