Genomic and epigenomic mechanisms of pediatric ocular disorders

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The Medical Genetics and Ophthalmic Genomics Laboratory has advanced the goals and objectives of the research program as follows: 1. Modeling novel associations of ocular syndromes with coding gene variation in zebrafish, mouse, and in vitro using CRISPR/Cas9 gene editing and developmental, molecular, and cellular biology investigations to elucidate disease mechanisms. We are currently modeling several new human disease genes in animal and cellular models. Two examples are CSDE1 (Guo et al, Science Advances, 2019), encoding a cold-shock domain containing RNA-binding protein, and UBA2 (Schur, Yousaf, Liu etc al, Genetics in Medicine, 2021), encoding a protein critical in SUMOylation. We have shown that, in both cases, haploinsufficiency in humans cause unique and recognizable neurodevelopemental disorders. Our group has also acted in collaboration to recently define multiple additional new disease-gene associations, including SMPD4, BMPR1A, and MYRF (see bibliography), in addition to multiple others in previous years. 2. Defining disease-associations in the noncoding genome and in eye tissues using functional genomics techniques. Using RNAseq, ATACseq, and Hi-C, along with single-cell sequencing technologies, we are mapping the active genome in human ocular cells derived from induced pluripotent cell lines for variant prioritization from human sequencing data. These transcriptomic efforts contributed to eyeIntegration, a public database for human sequencing data from ocular tissues and generation of predictive networks using machine learning (eyeintegration.nei.nih.gov; see bibliography).