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2017-01-27 / News

New study finds life-threatening genetic disorder is substantially underdiagnosed

DANVILLE, PA – A study conducted by Geisinger Health System in collaboration with the Regeneron Genetics Center (RGC) has found that a life-threatening genetic disorder known as Familial Hypercholesterolemia (FH) is both underdiagnosed and undertreated. It was published in the peer-reviewed journal Science on Dec. 23 alongside another significant study from the same Geisinger- RGC collaboration known as DiscovEHR. That foundational paper describes the exome sequencing and analyses of the first 50,726 adult participants in the DiscovEHR cohort – all members of the Geisinger MyCode Community Health Initiative.

In the FH study, the collaborators examined genetic variants causing FH in the DiscovEHR cohort and then compared the findings against the de-identified medical histories of these patients as contained in Geisinger electronic health records.

Traditionally, in the United States, FH is diagnosed in patients who have both high cholesterol and a family history of early heart attacks and strokes. Genetic testing for FH is currently uncommon in clinical practice.

FH is caused by a defect that makes the body unable to remove “bad” cholesterol from the blood. This cholesterol (low density lipoprotein cholesterol or LDL-C) then accumulates, often undetected, and can lead to early death from heart attacks or stroke – even in very young people.

Results of the new study found many undiagnosed cases of FH and helped to define the extent of FH in the general population and the extent to which it is systematically undertreated.

“The study shows us that FH is about twice as common as it was once thought to be, and that large-scale genetic testing for FH helps identify cases that would otherwise be missed,” said Michael F. Murray, M.D., Geisinger director of clinical genomics. “We now hope to use DNA sequencing to guide better management for patients.”

“FH is a serious disease that can have severe consequences for some people, but also has available treatment options,” said George D. Yancopoulos, M.D., Ph.D., president, Regeneron Laboratories and chief scientific officer, Regeneron. “We hope that this study will drive higher awareness of the prevalence of FH, since with greater vigilance more patients could be accurately diagnosed and treated with effective therapies.”

Among the many findings of the study were that 1 in every 256 people has a disease-causing mutation, or variant, in one of the three FH genes. It showed that participants with a deleterious FH gene variant had significantly higher “bad” cholesterol than those without an FH gene variant. They also had significantly increased odds of both general and premature coronary artery disease.

The study identified 35 mutations, or variants, in the genes that have been determined to cause FH: LDLR, APOB, and PCSK9. Only 24 percent of people who carry FH-causing variants had sufficient criteria within their electronic health records to support a probable or definite FH diagnosis, meaning that without genetic confirmation, many of these patients would go undiagnosed. Additionally, 42 percent of people with these FH-causing variants did not have a recent active prescription for statins, the first line therapy for cholesterol lowering. Among statin-treated people with FH- causing variants, less than half met goals for cholesterol lowering, suggesting the need for more intensive cholesterol- lowering therapy.

“We’ve focused on this condition for research at this time because of the Centers for Disease Control and Prevention’s (CDC) interest in this condition as a public health genomics priority, and the long-standing understanding that this condition goes undiagnosed in the vast majority of cases,” Murray said.

“Being able to connect patient’s de- identified medical records with their DNA data is an advantage that few others in this field have, particularly with this large number of patients. Paired with the RGC’s unique technological and analytical resources, we are able to make meaningful discoveries that may advance the implementation of precision medicine today and the development of new or improved medicines tomorrow,” said Noura Abul-Husn, M.D., Ph.D., associate director of translational genetics at the RGC and co-author of the paper. .

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