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. One example is CSDE1, a cold-shock domain containing RNA-binding program. We have shown that haploinsufficiency of this gene in humans causes a novel neurodevelopemntal disorder with autistic like features, short stature, relative microcephaly, and in some cases iris coloboma. This is consistent with contiguous gene deletions in humans, framing CSDE1 as the critical gene for 1p13.2 microdeletion syndrome. This manuscript is currently in press (Science Advances, 2019). Our group has also acted in collaboration to define multiple additional new disease-gene associations, including SMPD4, BMPR1A, and MYRF (see bibliography). 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).
