Identification and functional characterization of ultra-rare variants in childhood lupus - childhood-onset systemic lupus erythematosus (CSLE) is a rare, but often severe disease with multi-organ…

Identification and functional characterization of ultra-rare variants in childhood lupus - childhood-onset systemic lupus erythematosus (CSLE) is a rare, but often severe disease with multi-organ involvement and substantial long-term morbidity. While genome-wide association studies (GWAS) have identified numerous common risk loci, these variants explain only a fraction of the heritability and provide limited insight into the extreme phenotypes of CSLE. Emerging evidence suggests that ultra-rare, highly penetrant genetic variants may drive early-onset lupus and lupus-like autoinflammatory syndromes, but these variants remain largely uncharacterized. There is a critical unmet need to identify these potent drivers of pediatric autoimmunity to improve diagnosis, risk stratification, and development of targeted therapies. This fellowship encompasses an integrated research project and training plan to test the central hypothesis that highly penetrant, ultra-rare coding and non-coding variants disrupt critical regulatory pathways to drive the pathogenesis of CSLE. We propose a comprehensive genomic and functional approach to unravel this genetic architecture. Aim 1 will utilize whole genome sequencing (WGS) in a well-characterized cohort of families with one or more cases of CSLE, as well as sporadic CSLE cases, to identify highly penetrant ultra-rare coding variants (URCVS) and ultra- rare non-coding variants (URN-CVS). We will employ advanced bioinformatic pipelines to prioritize variants based on evolutionary conservation, predicted deleterious effects on protein structure or regulatory element function, and DE novo status. Aim 2 will define the functional consequences of high-priority URCVS by introducing patient-specific variants in human induced pluripotent stem cells (HIPSCS) using crispr-based genome editing. Differentiation of edited HIPSCS into immune-relevant lineages will allow direct assessment of variant-specific alterations in gene expression, cytokine signaling, and cellular phenotypes associated with lupus pathogenesis. This integrated genomic and experimental platform will provide new insight into the molecular architecture of CSLE, reveal new pathogenic mechanisms, and generate variant-linked cellular models that can be leveraged for therapeutic discovery. The proposed research will be conducted in an institutional environment that is enriched with research programs focused on autoimmune disease and human genetic and genomics, and supports state-of-the-art facilities, core laboratories, computational resources, and a vibrant scientific community. This environment, combined with strong research mentorship and a structured professional development plan, will foster my development into an independent physician-scientist equipped to pursue a research career in autoimmune genomics.