Exome sequencing identifies MLL2 mutations as a cause of Kabuki syndrome

Abstract

We demonstrate the successful application of exome sequencing to discover a gene for an autosomal dominant disorder, Kabuki syndrome (OMIM%147920). We subjected the exomes of ten unrelated probands to massively parallel sequencing. After filtering against existing SNP databases, there was no compelling candidate gene containing previously unknown variants in all affected individuals. Less stringent filtering criteria allowed for the presence of modest genetic heterogeneity or missing data but also identified multiple candidate genes. However, genotypic and phenotypic stratification highlighted MLL2, which encodes a Trithorax-group histone methyltransferase: seven probands had newly identified nonsense or frameshift mutations in this gene. Follow-up Sanger sequencing detected MLL2 mutations in two of the three remaining individuals with Kabuki syndrome (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.

Figure 1. Genomic structure and allelic spectrum of MLL2 mutations that cause Kabuki syndrome

MLL2 is composed of 54 exons that encode untranslated regions (orange) and protein coding sequence (blue) including 7 PHD fingers (yellow), FYRN (green), FYRC (green), and a SET domain (red). Arrows indicate the locations of 32 different mutations found in 53 families with Kabuki syndrome including: 20 nonsense, 7 indels, and 5 amino acid substitutions. Asterisks indicate mutations that were confirmed to be de novo and crosses indicate cases for which parental DNA was unavailable.