Developing a multi-omics approach to rapidly identify critical pathways and mechanisms in patients with pathogenic mutations in the gene KAT6A.
Understanding the role of chromatin modifiers in human development and disease started several years ago when I led a study first describing a novel genetic syndrome with global developmental delay and syndromic features that were caused by rare de novo mutations in the gene KAT6A. The KAT6A gene's major role is to acetylate histones and other proteins within a cell, allowing for the proper expression of RNA and proteins during human development. Within 4 years of our initial description in 2015, there are over 200 individuals worldwide with KAT6A Syndrome, making it a common causes of syndromic developmental delay. We recently published the largest study of KAT6A syndrome to date (Kennedy J, et al 2019 Genetics in Medicine) that described the mutational spectrum (Figure 1) and clinical phenotypes in 72 patients from around the world.
Figure 1. Mutations identified in 72 patients with KAT6A syndrome (Kennedy J, ...Arboleda VA* & Newbury-Ecob R* co-corresponding author, Genetics in Medicine 2018).
We have an active research program around KAT6A and related genes, as mutations in chromatin modifier genes typically have similar features, suggesting a related etiology. In the lab, we work to develop patient-specific model systems to understand how mutations directly effect the differentiation of brain and muscle cells’ genetic regulation. To do this, we have created induced pluripotent stem cell lines from patient’s with known pathogenic mutations in genes such as KAT6A, ASXL1 and other related chromatin modifier genes to better understand how the differentiation in brain-specific and heart-specific cells are affected by the patient mutations (Figure 2).
In addition to deriving patient-specific cell lines, we also use CRISPR-Cas9 systems to create specific patient mutations in human cell lines to study the effect of these genes on chromatin structure and gene regulation.
For patients, a great resource is that KAT6A Foundation, with whom we work closely with, to understand the clinical phenotype of KAT6A syndrome and develop clinical biomarkers for improved clinical variant interpretation.
If you are interested in contacting us to hear about the lab’s on-going research and how you might become involved, please fill out the form below and we will get back to you within 1-2 weeks.