Study of the Week: Some Genetic Tests Miss Familial Hypercholesterolemia

Welcome to Study of the Week from Patient Worthy. In this segment, we select a study we posted about from the previous week that we think is of particular interest or importance and go more in-depth. In this story we will talk about the details of the study and explain why it’s important, who will be impacted, and more.

If you read our short form research stories and find yourself wanting to learn more, you’ve come to the right place.


This week’s study is…

Limited variant screening vs comprehensive genetic testing for familial hypercholesterolemia diagnosis

We previously published about this research in a story titled “Familial Hypercholesterolemia Can be Missed on Some Gene Tests, Study Finds” which can be found here. The study was originally published in the science research journal JAMA Cardiology. You can view the full text of this study here.

What Happened?

Familial hypercholesterolemia is believed to be the most common inherited cardiovascular condition. However, it remains poorly understood, and the true number of patients is unknown. Many patients remain undiagnosed and while assay-based screenings can detect the condition in some patients, many only screen for a limited number of known pathogenic gene variants. The researchers sought to understand the extent of this issue and determine the number of variants that would be missed on array-based screenings.

Furthermore, they sought to compare the efficacy of these screenings to more detailed next-generation genetic sequencing. The results from a comprehensive genetic test were measured with an array screening that evaluated 24 known genetic variants. 4,563 people in the study underwent diagnostic testing for the condition and 6,482 people underwent next-generation sequencing. The researchers were looking for pathogenic or likely pathogenic (P/LP) variants.

Median age was 49 years, 55.4 percent were female, and 63.6 percent were of white/European ancestry. Under the limited-variant screening, the positive result rate was 8.4 percent; meanwhile, under the next-generation sequencing test, the positive rate was 27 percent. This means that 68.9 percent of positive results would have been missed with the limited-variant screening. These results were even starker in people of African or Latin ancestry, with 93.7 percent and 84.7 percent of positive cases being missed on the limited screening. This dropped to only 33.3 percent in Ashkenazi Jewish individuals.

Similar results were found in the cohort of proactive testing; 61.8 percent of positive cases would have been missed when using the limited-variant screening. Cascade screening, in which the first-degree relatives of a known familial hypercholesterolemia patient are also tested (a process commonly recommended) would have also been impacted by these findings.

About Familial Hypercholesterolemia (FH)

Familial hypercholesterolemia is a condition of elevated, abnormally high levels of LDL cholesterol that is caused by a hereditary genetic mutation. The mutation that causes the condition affects the LDLR gene which normally codes for a protein that removes LDL from the bloodstream. The primary symptoms are elevated LDL cholesterol, deposits of cholesterol in certain areas of the body (eyelids, iris, and tendons of the arms and legs), and early onset cardiovascular issues, such as coronary artery disease, strokes, heart attack, and atherosclerosis. While once considered rare, it is likely that many people with the condition live undiagnosed. Treatment may include statins or other medications, liver transplant, or other surgical operations. The true prevalence of familial hypercholesterolemia remains unknown. To learn more about familial hypercholesterolemia, click here.

Why Does it Matter?

The results of this study reveal a significant weakness in certain screenings that people concerned about familial hypercholesterolemia may use to guide their medical decisions. While most limited-variant assays are available commercially (ex. 23andMe) and are not as likely to be used in the clinic, the findings from this study nevertheless highlight the fact that not all tests are created equal and only comprehensive next-generation sequencing is sufficient for detecting all possible P/LP genetic variants that have been linked to the condition.

This concern is even greater for people of Latin or African ancestry, who saw far worse outcomes from limited-variant assay screenings. The findings represent a significant health disparity for these racial groups. As a whole, genetic testing is woefully underused by patients, with an estimated 90 percent being undiagnosed. It’s important for people who are seeking testing for familial hypercholesterolemia to seek input from a genetic counselor in order to understand the limitations and differences between different types of screenings.

Cardiovascular and heart diseases are the leading cause of death throughout much of the world. It is likely that familial hypercholesterolemia is having a greater impact than is currently understood, making proper detection of the condition essential to reducing rates of heart disease. Only then can patients receive proper treatment, and that means having reliable genetic testing available to anyone that is suspected of having the condition. 

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