PROJECT NARRATIVE The goal of the proposed research is to investigate how clinical genomic sequencing impacts families of pediatric patients. This research will develop an empirically informed framework of normative values important to families of pediatric patients, including ethical, legal, and social implications (ELSI), which will then be used to elicit preferences for features of sequencing from a nationally representative sample of parents in the US.

PROJECT NARRATIVE Though any single rare disease is by definition uncommon, together these diseases affect nearly 30 million individuals in the United States, two-thirds of whom are children, and contribute significantly to morbidity, mortality, and healthcare costs. Exome and whole genome sequencing have the potential to provide a diagnosis to an estimated 25 to 50 percent of those patients struggling with undiagnosed rare diseases, but the downstream costs and benefits of this testing beyond diagnosis remain largely unknown.

Project Narrative Currently, there are marked differences in variant classification among clinical laboratories, and genetic variant classification is currently in flux with improvements in the access to ethnically diverse reference data and new algorithms to predict the pathogenicity of variants. As variants are re-classified over time, there is currently no definitive guidance from professional organizations about how to handle this variant reclassification and who has the duty to re-classify variants and what those obligations are.

As genomic sequence data are being produced faster and at lower cost, the most significant challenge in clinical genetic testing today is variant classification. Currently, there are marked differences in variant classification among clinical laboratories, with clinically significant discrepancies in 29% of variants interpreted. Variants that were previously categorized as pathogenic are now known to be benign with the increasing availability of more ethnically diverse reference data, and this is issue is more common for individuals of non-European ancestry.