Robert B. Hufnagel, M.D., Ph.D.

Rob Hufnagel, a 2021 Lasker Scholar, is dedicated to understanding mechanisms of human genome variation that cause blindness in children. He uses a translational approach combining clinical molecular approaches and developmental biology to improve diagnosis and establish gene:disease and genotype:phenotype relationships. In particular, he uses genomics, stem cell engineering, and gene editing to establish patient-centered disease models for translational and preclinical studies. After receiving his M.D. and Ph.D. from the University of Cincinnati (Cincinnati, Ohio), he completed his Pediatrics and Clinical Genetics residency at Cincinnati Children’s Hospital, followed by fellowships in Clinical Ophthalmic Genetics at the National Eye Institute (NEI/NIH) and Clinical Molecular Genetics and Genomics at the National Human Genome Research Institute (NHGRI/NIH). He loves spending time with his family and their dog, Helix.

The goal of our research is to understand the mechanistic basis of human heritable ocular disorders, including those in children and adults with rare eye diseases and syndromes. Causal genetic variation explaining central vision loss in pediatric blinding disorders is poorly understood for two reasons. First, current clinical genetic testing strategies fail to provide a molecular diagnosis in a large proportion of patients. Our understanding of variant pathogenicity is limited both by the rare frequency of these disorders, preventing the creation of large disease-specific population studies, and by a lack of knowledge of the consequences of variation in the noncoding genome. Second, there are no established model systems for diseases of the macula and fovea, two neural retina specializations specific to the high acuity vision present only in humans, certain primates, lizards, and birds. Given that the macula and fovea are morphologically and molecularly distinct tissues, this creates hurdles to pre-clinical studies for gene-directed and cellular replacement therapies.

To address these needs, our research includes clinical molecular diagnostics (Ophthalmic Genomics Laboratory) from patients at the NIH clinical center and through the eyeGENE® program to develop population genomic datasets for rare eye diseases, coupled to scientific investigations (Medical Genetics and Ophthalmic Genomics Unit) validating candidate disease genes and mapping the disease-relevant noncoding genome of eye tissues. Model systems include human cells, mice, zebrafish, and foveate lizards. In this way, we are able to investigate the mechanisms of disease-causing genetic variants from bedside-to-bench using a broad array of tools. In turn, our work will better inform both molecular diagnostics and clinical trial design for treating these rare eye disorders.