Center for Pediatric Genomics

Projects & Collaborations

Heterozygous mutations in the KMT2D gene cause Kabuki Syndrome type 1 (KS1), a rare multi-organ disease where individuals suffer from developmental defects, including congenital heart defects, facial dysmorphism and intellectual disability. Here, we will use induced pluripotent cell system to understand the neurodifferentiation defects associated with KMT2D haploinsufficiency. This pilot project will provide a solid foundation for the study of the mechanism(s) behind neurodevelopmental defects in KS1 and allow identification of molecular targets for potential therapies.

Cholestatic liver diseases are characterized by failures of draining bile from the liver and represent the majority of liver diseases in children. About 30% of children with cholestasis do not have a molecular diagnosis, hindering effective treatment. We previously associated rare deleterious variants in ABCC12, which encodes a novel transporter MRP9, with intrahepatic cholestasis. In this application, we will investigate the roles of MRP9 in cholangiocyte health and test if MRP9 deficiency is a novel risk factor in biliary fibrosis, the common final pathway of cholestatic liver diseases in children.

Mutations in the GNAQ gene are a cause of childhood vascular tumors. These vascular tumors are very disfiguring and can be life-threatening. However, there are no FDA-approved treatments available that specifically target tumor biology. Using a new genetic mouse model and adeno-associated viruses (AAVs) that preferentially infect tumor-forming endothelial cells in blood vessels, the Boscolo and Robinson labs in the Division of Experimental Hematology and Cancer Biology will design and test a novel targeted gene therapy for GNAQ-driven vascular tumors in GNAQ mutant mice. If successful, this CpG Pilot Award will provide proof-of-concept results that are needed to support further development of AAV-based treatments for GNAQ-mediated vascular tumors.

Mechanical circulation (heart-lung machines), which includes extracorporeal membrane oxygenation (ECMO) and cardiopulmonary bypass (CPB), are lifesaving devices that provide support for patients with heart and lung failure, as well as patients undergoing complex open-heart surgery. Unfortunately, ECMO and CPB can be complicated by serious blood clots and immune system dysfunction, both of which can cause life-threatening organ damage. Our studies in animal models indicate that these clotting and immune side effects are linked through a clotting system protein called factor XII. Unlike other proteins in the clotting system, we can eliminate factor XII without creating any bleeding risks, making it a potentially exciting target for new therapies. The studies in our CpG grant will use cutting-edge genetic technologies to define the effects of factor XII and mechanical circulation on individual immune cell subtypes in molecular detail, providing critically needed information regarding how mechanical circulation and factor XII alter immune functions. We are excited by the potential of the studies funded by this grant to lead to new ways to treat and/or prevent the dangerous clotting and immune sequalae associated with ECMO and CPB.

Food allergy is a potentially life-threatening condition. Current diagnostic tests either have poor accuracy or carry considerable risk and cost. We plan to address this unmet need by developing novel diagnostic biomarkers by interrogates the cell types responsible for producing this inappropriate food reactivity.

Genetic variants in the human SOX10 gene cause serious congenital syndromes affecting pigmentation, digestion, hearing, and neural function. This pilot project will trace the source of an additional unexpected symptom found in a new sox10 animal model: severely deficient bone mineralization associated with disrupted systemic mineral regulation. Findings will have relevance for patients with SOX10 variants, as they may harbor subclinical symptoms that could be targeted to improve clinical outcomes.

Pioneer transcription factors (TFs) play a crucial role in regulating cell fate by establishing transcriptionally active states. However, cell fate control requires the coordination of both gene activation and repression, a process that is poorly understood. To fill this gap, we will systematically determine the gene regulatory principle of pioneer TFs and repressors cooperating on thousands of cis-regulatory sequences, utilizing perturbation-based Massively Parallel Reporter Assays and DiMeLo-seq (Directed Methylation with Long-read-seq for mapping protein-DNA interaction). Our studies will ultimately enhance precise manipulations of cell fate in regenerative medicine.

Genetic screens are performed for many diseases, but their power is dampened by frequent findings of alterations that have unknown effects on the function of the encoded protein; these are termed variants of uncertain significance (VUS). Here we focus on ataxia-telangiectasia (A-T), a devastating disease that typically afflicts children and which often targets the nervous system and increases the risk of developing cancer. A-T is associated with changes in the ATM gene. VUS diminish the capacity of screens of the ATM gene to aid early diagnosis and the implementation of appropriate treatments. Thus, in this CpG pilot project, we will establish a high throughput system for in vitro tests to help interpret the clinical impact of ATM VUS, thereby benefiting A-T patients and their families.