A life-threatening genetic disorder called as Familial Hypercholesterolemia (FH) is both underdiagnosed and undertreated says a recent study conducted by Geisinger Health System in collaboration with the Regeneron Genetics Center (RGC).

It was published alongside another important study from the same Geisinger-RGC collaboration called as DiscovEHR. That other study explains exome sequencing and analyses of the initial 50,726 adult participants in the DiscovEHR cohort — all members of the Geisinger MyCode Community Health Initiative.

In the FH study, the researchers observed genetic variants causing FH in the DiscovEHR cohort and then compared the results against the de-identified medical histories of these patients as present in Geisinger electronic health records. Conventionally, in the United States, FH is diagnosed in patients with high cholesterol who also have a family history of stroke and early heart attacks. Genetic testing for FH is now rare in clinical practice.

FH is caused by a defect that makes the body incapable of eliminating “bad” cholesterol from the blood. This low density lipoprotein cholesterol or LDL-C then builds up, frequently undetected, and can result in early death from heart attacks or stroke, even in very young patients.

Findings of the recent study discovered many undiagnosed cases of FH and described the extent of FH in the general population.

Hypercholesterolemia and medical records

“The study explains to us that FH is about twice as frequent as it was once thought to be, and that large-scale genetic testing for FH facilitates detecting cases that would otherwise be missed,” noted Michael F. Murray, M.D.,who serves as Geisinger director of clinical genomics. “We currently hope to use DNA sequencing to have better management for patients.”

Among the various findings of the study are that one in every 256 people have a disease-causing mutation, or variant, in one of the three FH genes. It described that participants with a toxic FH gene variant had considerably higher “bad” cholesterol levels than those lacking an FH gene variant. They also had remarkably raised chances of both general and premature coronary artery disease.

“Accessing patients' that are de-identified medical records with their DNA data is a benefit that few others in this field have. Combined with the RGC’s exclusive technological and analytical resources, we are able to make significant discoveries that may lead to the implementation of precision medicine today and the development of new or advanced medicines tomorrow,” mentioned Noura Abul-Husn, M.D., Ph.D., associate director of translational genetics at the RGC and the co-author of this paper.

The study recognized 35 mutations, or variants, in the genes LDLR, APOB, and PCSK9 that have been verified to cause FH. Only 24 percent of people who carry FH-causing variants had enough criteria within their electronic health records to help make a probable or definite FH diagnosis, meaning that without genetic verification, many of these patients would go undiagnosed and are likely to be undertreated. Certainly, 42 percent of people with these FH-causing variants did not have a current active prescription for statins, the primary therapy for lowering cholesterol levels. Among those statin-treated people with FH-causing variants, only about a half of the population met goals for cholesterol lowering.

“Geisinger is dedicated to translating this significant research directly into advanced care for our patients,” said Geisinger Executive Vice President and Chief Scientific Officer David H. Ledbetter, Ph.D. “We have started a key effort to verify individual patient findings and notify individual participants and their doctors when genetic findings, that are known to cause illness, are discovered in our population,” he stated.

FH is one of the 27 genetic conditions being aimed at Geisinger. So far, nearly 200 patients — together with 29 FH carriers — have previously been reported to carry one or more disease-causing genetic mutations with consequences that can be treated. These conditions are mostly linked to risk for cancer or cardiovascular illness. The effort to return individual results will carry on as more results are verified.

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