Molecular Genetics of Kabuki Syndrome

Abstract Kabuki syndrome (KS) is a rare, multiple congenital anomalies/mental retardation syndrome characterised by a peculiar face, skeletal abnormalities, cardiac anomalies, and immunological defects. Exome sequencing identified MLL2 mutations as a major cause of KS. MLL2 is a member of the Mixed Lineage Leukaemia (MLL) family of histone methyltransferases, essential in the epigenetic control of active chromatin states. MLLs act as transcriptional co‐activators in embryogenesis and development. As a significant proportion of patients do not have any MLL2 mutation, the existence of additional genes associated with this syndrome was postulated. By Comparative Genomic Hybridisation (CGH) array, de novo partial and/or complete deletions of KDM6A gene have been identified in a small group of MLL2 ‐mutation‐negative Kabuki patients. Notably, KDM6A codes a histone demethylase that interacts with MLL2. Overall, these findings suggest that Kabuki syndrome is a genetic heterogeneity disease and highlights the growing role of histone methylases and histone demethylases in multiple congenital anomalies and intellectual‐disability syndromes. Key Concepts: Kabuki syndrome is a rare, multiple malformation disorder characterised by a distinctive facial appearance, cardiac anomalies, skeletal abnormalities, and mild to moderate intellectual disability. Kabuki syndrome is an autosomal dominant condition that de novo arises in the majority of patients. It is phenotypically variable and genetically heterogeneous. Whole exome sequencing identified mutations in MLL2 gene in approximately 70% of the Kabuki patients. The MLL2 gene encodes a multiple domain‐containing protein that methylates the Lys‐4 position of histone H3 (H3K4), an epigenetic mark correlated with transcriptional active chromatin. Approximately 70% of MLL2 mutation‐positive KS patients carry truncating mutations predicted to result in haploinsufficiency or nonfunctional MLL2 protein. In a search for an additional gene causing Kabuki syndrome, microdeletions of the KDM6A gene were identified in three MLL2 ‐mutation‐negative Kabuki patients. KDM6A is a histone demethylases that interacts with MLL2. Histone methylases and histone demethylases are key‐genes involved in multiple congenital anomalies and intellectual‐disability syndromes.