Grant: Project Grant

KAT6A and KAT6B are two closely related human genes. Changes in these genes can cause a wide range of neurological and developmental problems in children, including developmental delay, intellectual disability, movement difficulties, seizures, and autistic features. Even within the same gene, symptoms can differ greatly from one child to another. Many families still receive uncertain genetic results, making it difficult to know whether a specific variant is actually causing disease. We still know very little about why different changes in KAT6A or KAT6B lead to such different outcomes. One major reason is that there are very few animal models that test the effects of individual patient variants. Our team has generated preliminary data in fruit flies showing that we can measure the effects of patient-specific KAT6A and KAT6B variants. These flies can act as "humanized patient avatars," allowing us to test how different variants alter gene function in a living organism. Our results already suggest that different KAT6A/B variants do not all behave the same way, which may help explain why patients show different symptoms and may eventually support more tailored treatment strategies. In this study, we will generate and study fly models carrying KAT6A/B variants from about 100 individuals. We will use these models to: (1) determine how different variants affect gene function and contribute to different clinical outcomes; (2) help clarify variants of uncertain significance identified locally and in public databases; and (3) test whether drugs that affect epigenetic pathways can improve movement and seizure-like problems seen in our fly models. For each aim, we will also perform complementary studies in human cells. By testing individual variants in living models, this work will help explain why children with KAT6A/B-related conditions can be affected so differently and will improve the evidence needed for diagnosis, prognosis, and future precision therapies.