Principle Investigator: Rulan Jiang, PhD

Rulang Jiang.Kabuki syndrome (KS) is a multisystemic congenital disorder characterized by distinctive dysmorphic facial features including cleft palate, congenital heart defects, skeletal anomalies, intellectually disability and immune dysfunction. Given the multi-organ congenital anomalies, many KS patients face a multitude of early life challenges, enduring several rounds of surgical repair during the first years of life. Unfortunately, immune dysfunction and repeated infections often emerge as the patient stabilizes and begins to grow, causing significant morbidity and even mortality.

Although KS has become a well-documented pediatric disease and most KS cases have been associated with mutations of the KMT2D gene, much of the pathogenic mechanisms remains unclear. With our collaboration of four research laboratories with diverse expertise in genomics / epigenomics, developmental biology, stem cell biology, and pediatric immunology, we will work to unravel the developmental and pathogenic mechanisms, using both patient-derived induced pluripotent stem cell models and tissue-specific conditional gene-knockout mice. Results from this research will not only improve the understanding of the pathogenic mechanisms but also provide new diagnostic and therapeutic targets for improving clinical care of KS patients.

The normal product of the KS disease gene, KMT2D, is a component of protein complexes involved in modifying chromatin to activate gene expression in multiple developmental processes. Recently, the increasing use of exome-sequencing in clinical diagnosis have revealed mutations in several other components of the same or related chromatin modifying complexes in a number of previously uncharacterized and clinically overlapping congenital syndromes. Thus, the knowledge gained in this study about the pathogenic mechanisms underlying KS will lead to significant improvement in diagnosis, treatment, and care of patients with pediatric epigenetic diseases in general.