Deletion of KDM6A, a Histone Demethylase Interacting with MLL2, in Three Patients with Kabuki Syndrome

TLDR

Kabuki syndrome is a rare genetic disorder causing developmental delay and congenital anomalies, with MLL2 mutations accounting for 56–76 % of cases and suggesting additional genetic contributors. We identified de novo deletions of KDM6A in three Kabuki syndrome patients, demonstrating that loss of this histone demethylase is a novel pathogenic mechanism and underscoring the importance of histone methylation regulators in the syndrome.

Abstract

Kabuki syndrome (KS) is a rare genetic disease that causes developmental delay and congenital anomalies. Since the identification of MLL2 mutations as the primary cause of KS, such mutations have been identified in 56%–76% of affected individuals, suggesting that there may be additional genes associated with KS. Here, we describe three KS individuals with de novo partial or complete deletions of an X chromosome gene, KDM6A, that encodes a histone demethylase that interacts with MLL2. Although KDM6A escapes X inactivation, we found a skewed X inactivation pattern, in which the deleted X chromosome was inactivated in the majority of the cells. This study identifies KDM6A mutations as another cause of KS and highlights the growing role of histone methylases and histone demethylases in multiple-congenital-anomaly and intellectual-disability syndromes.