Genomic Ascertainment - Clinical and Behavioral Aspects

National Human Genome Research Institute

Investigators

Linked publications, trials & patents

Abstract

Predictive genomic medicine or precision genomic medicine is of the highest medical importance and is an active area of research. We began piloting the return of genome-wide rare variants with the inception of the ClinSeq program in 2006, well before exome and genome sequencing became widespread (Biesecker et al., Genome Res 2009). We have continually expanded our work in this area by searching the genome for high penetrance variants that could be useful for clinical care, reproductive risks, pharmacogenetics, and other uses. My vision is that the genome is a health care resource, not a test, and that the cost of this health care resource can be amortized over the lifetime of an individual, long after its primary indicated usage is accomplished. Indeed, it was our work on ClinSeq that undergirded the recommendations we made for secondary findings (opportunistic screening) that were released in 2013 (Green et al., Genet Med 2013) These recommendations were initially highly controversial but with some amendments have now settled into accepted clinical practice an example of how we aim to change the practice of medicine. This paper has been cited more than 1,200 times and has also become the basis of a number of clinical testing laboratories health screening gene sets. ClinSeq has also been a leader in demonstrating to the field that genomes and exomes can be analyzed in healthy people and results returned, with minimal adverse consequences, dispelling the widespread fears about anxiety, depression, health care over-utilization, and other hypothetical risks. Genomic medicine has at its foundation prediction predicting phenotype based on genotype. To address this foundational challenge, we need to develop research modes that can model and test the predictive power of genomic variants. Resources such as gnomAD provide critical data on population prevalence but are seriously limited with respect to phenotype data. The UK BioBank is supporting genotype ascertainment, but its data are limited to pre-hoc phenotypes and blood samples and participants cannot be re-contacted. There is thus a compelling need for the capacity to perform bespoke phenotyping based on genotypes. Our major effort here is the Genomic Services Research program where we have engaged with 15,000 individuals who have received a secondary finding. We have fully evaluated several hundred of these individuals and developed a new metric for assessing the diagnostic power of a secondary finding. Another major bottleneck in predictive genomic medicine is the return of results. The standard clinical model is for a physician or genetic counselor to meet with a patient for an individual session to describe the results, review the clinical implications, and provide genetic counseling and/or recurrence risks. This is obviously not scalable, and the field is in urgent need of alternative approaches to this challenge the variants from an exome (much less a genome) cannot be returned to a participant with this model. While most presume that this means that exomes and genomes need to be throttled or filtered down to just a single or few clinically relevant variants that can be returned using the standard model, the question should be asked as to whether alternative means to results return can be devised. We have now undertaken a major project to provide phenotyping for individuals suspected to have malignant hyperthermia susceptibility in collaboration with NIHCC neurosurgery and the USUHS ex vivo muscle testing laboratory.