Findings from a recent study by University of Pennsylvania and Invitae researchers suggests limited variant screening for familial hypercholesterolemia, as provided in available direct to consumer (DTC) tests, could lead to many people with this condition remaining undiagnosed.

The authors argue in their JAMA Cardiology article that more comprehensive testing would be a better option for people at risk of the cardiovascular condition, as less cases would be missed.

“The main problem is that DTC tests can give false reassurance,” Invitae’s Chief Medical Officer Robert Nussbaum, an author on the paper, told Clinical Omics.

“This means that for the majority of people looking for a change in a gene that would impact their health, the change would not be picked up, and they would receive a false negative result.”

Familial hypercholesterolemia (FH) is a genetic condition that results in people having high levels of low-density lipoprotein (LDL) cholesterol, so-called ‘bad’ cholesterol, that can dramatically increase a person’s risk of developing early cardiovascular disease if left undetected.

The most common genetic variants causing FH are LDLR gene mutations, which can occur in as many as 1 in 250 people, although not all carriers will show symptoms. But FH is a genetically heterogeneous condition, with many causal variants recorded in the literature.

Notably, as many as 90% of individuals with FH remain undiagnosed. Testing and diagnosis of this condition is important, as treatments such as statins and lifestyle changes can help reduce the risk of cardiovascular events if introduced early enough.

While many people may go through a clinician or genetic counselor to get tested with more extensive tests like the ones offered by Invitae, DTC tests are also available such as 23andMe’s 24 variant FH test.

In this study, the researchers screened two cohorts of people for FH—4,563 that were thought to be at risk for FH and were referred for testing by their clinician and 6,482 people taking part in a proactive genetic testing study searching for variants in a number of genes and indications including FH.

The more in-depth Invitae test used in the study screened for up to 2,000 variants linked to FH in the genes LDLR, APOB, PCSK9, and LDLRAP1, and was compared with 23andMe’s 24-variant FH test, which screens for 23 variants in LDLR and one in APOB.

The Invitae test picked up carriage of FH risk variants likely to cause disease in 27% of the at-risk cohort. In comparison, the 23andMe test would have picked up 8.4% of the risk variants detected. In the proactive test group 34 individuals were detected as having FH variants that could cause disease and the researchers say that 21 of these would have been missed if the 23andMe test was used.

There has been a lot of argument about whether DTC testing is a good or bad option for patients. Genetics is a complicated topic and clinicians and other health care providers such as genetic counselors can help people who are tested interpret their results properly and get a better idea of their actual disease risks.

“DTC tests are not based on a complete analysis of the entire gene and therefore miss many changes that are medically important that would be picked up by a medical test like the one offered by Invitae,” says Nussbaum. “Our published study is meant to warn clinicians and consumers not to take a negative DTC result as a negative.”

However, due to the importance of treatment and the high number of undiagnosed people with FH in the population, it can be argued that even if the test is limited it can still help people get the right medical care.

“As the authors point out, even with its limitations, DTC genetic testing for FH has the potential to exceed the number of individuals identified via comprehensive clinical testing due to how many people are pursuing DTC genetic testing,” Stacey Detweiler, Medical Affairs Associate II at 23andMe told Clinical Omics.

“Specifically, over 7,000 23andMe Health + Ancestry customers have been found to have one of the FH variants tested. Given that about 90% of those with FH are undiagnosed, it is likely that many of these individuals were previously unaware of their risk.”

Another common concern about DTC tests is whether or not individuals ordering these tests are properly informed about what their test results may mean, but 23andMe says that making sure their customers are fully informed is very important for the company.

“In order to obtain FDA authorization for 23andMe’s Genetic Health Risk reports, we had to demonstrate that consumers can understand the reports and their limitations. For the Familial Hypercholesterolemia Genetic Health Risk report specifically, there is language throughout highlighting the number of variants tested, the ethnicities that are most relevant, the importance of talking with a healthcare professional should a customer have a personal or family history of high cholesterol or early heart disease, and the fact that customers could still have a variant not included in this test,” said Detweiler.

“Customers are also required to view an educational tutorial prior to accessing any Genetic Health Risk report that highlights key limitations and concepts relevant for all reports in this category.”

An important point in favor of more in-depth testing as it can help to overcome issues such as European bias in test results – something that is common across human genetic testing, as many initial cohorts currently available tests are based on are largely of white European origin. Indeed, the 23andMe test was predicted to miss 93.7% of FH variants in Black or African American individuals and 84.7% of the FH variants in Hispanic individuals detected in the JAMA Cardiology study.

While it is true that the ideal situation may be to carry out tests via a medical referral, this can be expensive, is not always available, and is not always covered in medical insurance policies.

“In some ways, DTC testing is a reflection of the lack of commitment of the medical community to provide genetic screening to patients as part of their primary care,” said Nussbaum.

“The good thing about DTC screening is that it has helped show people the importance of understanding their DNA, and encouraged people and made it easy for them to seek answers for genetic risk for breast cancer or heart disease – even though the answers are limited and don’t fully answer the questions consumers are asking,” he explained.

23andMe openly acknowledges that its test does not test for all FH variants and advises customers about the importance of talking with a healthcare professional about their results, but says its test is still a valuable option for those interested in knowing their FH status.

“One huge benefit of a screening tool like 23andMe is that it can help identify risks for people who have been missed by the traditional healthcare system, including those who may not qualify for clinical testing,” emphasized Detweiler.