Sequencing ever-larger datasets of human exomes - and
full genomes - has become faster, more accurate, and less expensive. Therefore,
researchers can find rare genetic variants more quickly. And then
matching these rare genetic finds to electronic health record (EHR) phenotype data has the
potential to inform health care in important ways, suggests a new study.
"The value of intersecting the sequencing of individuals' exomes (all
expressed genes) or full genomes to find rare genetic variants - on a
large scale - with their detailed electronic health record (EHR)
information has myriad benefits, including the illumination of basic
human biology, the early identification of preventable and treatable
illnesses, and the identification and validation of new therapeutic
targets," wrote Daniel J. Rader, chair of the Department of
Genetics, in the Perelman School of Medicine at the University of
Pennsylvania, in Science
, with Scott M. Damrauer, an assistant professor of Surgery at Penn and the Veterans Affairs
Medical Center in Philadelphia.
‘These efforts will one day reveal the fundamental value of what the genome contains for health and disease and pave the way for precision medicine.’
Their commentary accompanies two linked studies on the topic in the
One reports on whole-exome sequencing of more than 50,000
individuals from the Geisinger Health System in Pennsylvania and the
analyses of rare variants with data from longitudinal electronic health
records. They identified hundreds of people with rare
"loss-of-function" gene variants that were linked to observable
physiological characteristics, or phenotypes.
The second article reports
on a study that identified individuals in the same database with
familial hypercholesterolemia, many of whom had not been diagnosed or
"These results demonstrate the enormous potential of this approach
for promoting scientific biomedical discovery and influencing the
practice of clinical medicine," the authors wrote.
"Many single-gene disorders like familial hypercholesterolemia [FH]
are under-diagnosed," Rader said. "Once an individual with a single-gene
disorder is identified, not only can that person be placed on
appropriate medical intervention, but we can also screen his or her
extended family members to see who else carries the mutant gene and may
benefit from preventative approaches."
He cites a recent list of 59
"medically actionable" genes, curated by the American College of Medical
Genetics and Genomics (ACMG), in which loss of function mutations can
lead to specific medical interventions. For example, individuals from
the extended family of a person found to have FH who also carry the
mutation should have their cholesterol checked and be placed on
medication to reduce cholesterol.
"Identifying rare variants can also contribute to our understanding
of more common, complex disorders such as Type 2 diabetes or chronic
kidney disease," Rader said. "These efforts will one day reveal the
fundamental value of what the genome contains for health and disease and
pave the way for precision medicine in every clinic and hospital."