Exome sequencing identified MLL2 mutations as a cause of Kabuki syndrome. Ten unrelated individuals with Kabuki syndrome were sequenced, revealing mutations in MLL2 in seven cases. Follow-up Sanger sequencing confirmed MLL2 mutations in 26 of 43 additional cases, with mutations being de novo in 12 cases and inherited in 2. MLL2 encodes a large protein involved in histone methylation and epigenetic regulation. Mutations in MLL2 were found in 33 distinct mutations in 35 of 53 families, with 90% of the discovery cohort having MLL2 mutations. MLL2 mutations were confirmed to be de novo in 12 cases. The study suggests that MLL2 mutations are a major cause of Kabuki syndrome. The findings highlight the importance of exome sequencing in identifying genetic causes of rare diseases. The study also emphasizes the need for further research to understand the genetic heterogeneity of Kabuki syndrome and to identify additional genes involved. The results demonstrate the power of exome sequencing in discovering the genetic basis of complex diseases.Exome sequencing identified MLL2 mutations as a cause of Kabuki syndrome. Ten unrelated individuals with Kabuki syndrome were sequenced, revealing mutations in MLL2 in seven cases. Follow-up Sanger sequencing confirmed MLL2 mutations in 26 of 43 additional cases, with mutations being de novo in 12 cases and inherited in 2. MLL2 encodes a large protein involved in histone methylation and epigenetic regulation. Mutations in MLL2 were found in 33 distinct mutations in 35 of 53 families, with 90% of the discovery cohort having MLL2 mutations. MLL2 mutations were confirmed to be de novo in 12 cases. The study suggests that MLL2 mutations are a major cause of Kabuki syndrome. The findings highlight the importance of exome sequencing in identifying genetic causes of rare diseases. The study also emphasizes the need for further research to understand the genetic heterogeneity of Kabuki syndrome and to identify additional genes involved. The results demonstrate the power of exome sequencing in discovering the genetic basis of complex diseases.