Rare diseases individually affect fewer than 200,000 people but collectively impact 1 in 10 Americans, including 16 million children. Most lack treatments and diagnosis can take five years—a critical delay since 30% of affected children may not survive past age five.

Challenges in diagnosing and treating rare pediatric disorders could be addressed by grouping them based on shared characteristics. Different mutations may affect the same biological process, leading to similar health issues. By targeting these common processes instead of individual mutated genes, we can identify therapies that benefit multiple rare diseases. Our project focuses on two rare genetic disorders: Kabuki Syndrome and KAT6A Syndrome, which impair brain development and can cause heart problems in children. These conditions result from mutations in the genes KMT2D and KAT6A, which modify histone proteins that regulate gene activity. However, how these mutations affect cell function is not understood, obstructing the development of treatments and the ability to predict disease progression.

We aim to identify unique “fingerprints”—histone modification patterns—caused by these mutations. Our method, EpiFlow, suggests that mutations in KMT2D and KAT6A lead to specific histone patterns that vary by cell type. We will investigate which histone changes result from reduced levels of these proteins, how they impact different cell types, and whether each patient has a unique pattern linked to disease severity. Our approach uses lab-grown stem cells where we control KMT2D and KAT6A protein levels in brain and heart precursor cells to study histone patterns. Additionally, we will examine patient blood cells for unique histone patterns, analyze gene activity, and identify DNA regions associated with the disease.

Our research could help doctors predict the severity of Kabuki Syndrome and KAT6A Syndrome in children, allowing for personalized care. By understanding the cellular changes caused by these mutations, we aim to identify new targets for future therapies, leading to better outcomes and improved quality of life for affected children. Furthermore, our findings could enhance understanding of other rare diseases that affect similar biological processes, potentially benefiting a broader range of patients.