Nicholas Katsanis

Genome-wide sequencing is emerging as a powerful tool as a first-pass diagnostic test. This has heightened the need for interpretive assays to determine the pathogenic potential of genetic variation. To address these challenges, and to capitalize on the opportunity to shorten the time to secure molecular diagnoses, we have created the Task Force for Neonatal Genomics at Duke University. The Task Force targets a uniquely vulnerable patient cohort: infants and neonates whose developmental anomalies are more likely to be within a timeframe for treatment. Our efforts harness the full spectrum of clinical, genetics and cellular biology expertise, including the use of transient model organisms (primarily zebrafish). I will discuss: 1) the interdisciplinary nature of our efforts; 2) our methodology for recruitment, data generation and analysis, and communication strategies between researchers and clinicians; 3) our analysis progress to date; and 4) our evolving approach to returning primary and secondary molecular findings to clinicians and family members. In phenotype-appropriate patients, we couple whole exome sequencing of trios, a multi- tiered bioinformatic prioritization strategy, and functional modeling of novel variants in physiologically relevant vertebrate and cell-based models to inform allele pathogenicity. Strikingly, in our first year, we have achieved definitive diagnoses for 41% of our patients and strong candidate diagnoses that typically involved novel disease genes and/or complex genetic interactions in 78% of our cohort. This initiative provides an unprecedented model for communication across an interdisciplinary research/clinical team with the ultimate goal of responsible and timely integration of new genetic technologies into clinical care.