DNA Testing Kits

The Promise and Peril of Consumer Genetic Reports

Understanding the limitations of the reports from places like 23andMe

Direct-to-consumer genetic testing is widely available and reasonably priced. Although many companies primarily use genetic analysis to determine ancestry, others are using the information to develop lifestyle and medical guidance reports. This sounds wonderful and incredibly useful. In principle, the reports can help a person make informed decisions about disease risks and help their doctors optimize treatment plans. This is the holy grail of precision medicine, tailoring a person’s therapy based on their medical history, symptoms, and genetics.

But these reports can be misleading in ways that can be dangerous. For example, the reports are incomplete. Sometimes this lack of information occurs because all of the genetic variations that can contribute to disease or differences in drug responses are unknown. Other times the information is known, at least in the medical literature, but it is not included in the report. The first type of omission is unavoidable until new data are available that can be added into the databases and used to generate updated reports. The second type are avoidable. Both are types of omissions can be life threatening if decisions are based on a report stating the absence of a genetic risk variation.

Consider this example. A condition commonly called Favism is a genetic disease caused by mutations in the gene for the enzyme glucose-6-phosphate dehydrogenase (G6PD). The mutations cause G6PD deficiency, too little of activity of this enzyme. The main symptom of the disease is a form of anemia called hemolytic anemia. This means that the red blood cells literally explode (in science terms “lyse”), compromising the ability of blood to carry oxygen.

The G6PD gene has several mutations, referred to as variants or single nucleotide polymorphisms (SNPs). The variants are divided into 5 classes based on how much they alter the activity of the enzyme. People with class 1 variants have the least G6PD activity and will be chronically anemic, and those with class 2 variants have G6PD deficiency. Those with class 3 and 4 variants have more enzyme activity than either those with class 1 or 2 variants, although still less than people without any of these variants. Only those with class 1 variants have symptoms, the people with the other classes often do not have any symptoms. Indeed, some of the variants are common in populations where malaria is common, because the mutations provide some protection against malaria.

However, in anyone with G6PD deficiency from class 1 through class 4, eating some foods, such as fava beans, or taking certain medications can trigger a life-threatening hemolytic crisis that requires blood transfusions. Despite this risk, testing for G6PD deficiency is not routinely done in all newborns in the US.

With this information in publicly available databases, companies providing genetic testing for consumers can include information on G6PD deficiency in health reports. Indeed, 23andMe includes information about G6PD deficiency risk in their health report. However, those reports may not be complete, as is the situation for the 23andMe report.

Consider this case of a young man with a mother who is half Ashkenazi Jew and a father whose ancestry is Northern European. Although Ashkenazi Jews tend to have higher incidences of some genetic diseases, Favism is not one of them. Because the G6PD gene is on the X chromosome, boys inherit this gene from their mothers.

He had his wisdom teeth removed before going away to college, received prophylactic antibiotics, and then developed blood in his urine. The doctor at an urgent care center changed the antibiotic to Bactrim to treat what was thought to be a urinary tract infection. The amount of blood in his urine increased until his urine was bright red. At this point, he saw his primary care physician who found that his oxygen had dropped to 75%. Any level below 90% is considered hypoxic. The 75% level was so low that the doctor had him transported to the hospital by ambulance so that he could be placed on oxygen immediately.

At the hospital, the doctors were focused on his liver and kidneys, performing imaging tests and blood tests looking for a source of the anemia. The doctors did not consider medication-induced hemolytic anemia due to G6PD deficiency a possible cause of his condition. The amount of hemoglobin, the protein that is in red blood cells that carries oxygen, kept dropping. Even on oxygen, his oxygen levels only reached 80%. Ultimately, a hematologist was called in, and a test for GP6D in his blood was ordered. Unfortunately, the test results took 2 days and were not conclusive for someone in a hemolytic crisis. For someone in a hemolytic crisis, the amount of G6PD is higher than it would normally be. While waiting for the results of the G6PD test, he continued to worsen, developing jaundice and a falling blood pressure as his body struggled with the blood loss. The doctors gave him 3 blood transfusions over the next few days.

Fortunately, his mother is a scientist. While the doctors were running tests, her son was receiving blood transfusions, and they were waiting for a diagnosis, she started researching causes of hemolytic anemia. She found a scientific article that described Favism and how it could be triggered by certain medications.

The gene causing G6PD deficiency is on the X chromosome. This means that she would have given her son’s X chromosome. Fortunately, she had her DNA tested by 23andMe. So, she looked at her health report for G6PD deficiency. The report said that she did not have the variant.

23andMe report showing G6PD deficiency variant was not detected.

From her research, she knew that there were several variants that could cause G6PD deficiency. Again, her son was lucky, because she was knowledgeable enough to look at the DNA data herself and then do more research to see if the DNA data indicated that she had one of the Favism mutations. Sure enough, she carried a variant that causes class 2 G6PD deficiency. In scientific terms, she had the SNP “rs5030868,” which changes a single guanine to an adenine in the G6PD gene and causes a single amino acid change in the G6PD enzyme, a serine at position 188 is a phenylalanine (S188F). This means that her son’s hemolytic crisis was triggered by the antibiotic and exacerbated by switching to Bactrim.

G6PD SNP report with the disease-causing variant outlined in red.

She also has G6PD deficiency. It is likely that her disease is less severe than her son’s, because she likely only has one copy of the variant. Her other X chromosome could have a normal copy of the gene. She would require additional testing to determine this, because it is not information provided by 23andMe and it cannot be determined from the SNP results. As a male with only one X chromosome, her son only has the class 2 deficiency gene variant.

If she had relied on the “Health Disposition” report, she would have told her son that he was not at risk of G6PD deficiency. He would not know that he had to avoid certain medicines, including the antibiotic that triggered his life-threatening medical emergency. He may not have the variant included in the Health Disposition report, but he clearly has a variant that causes class 2 G6PD deficiency.

Understanding exactly what variants any genetic testing service evaluates and provides in their genetic risk report is critically important. In this case, 23andMe only evaluates DNA for a variant that changes a valine to a methionine at position 68 in the protein. This is a variant that found in people of African descent or people with African ancestry. The company does not report on variants that are common in people of Mediterranean, Middle Eastern, Asian, or Kurdish Jewish descent. 23andMe explain this on their website in the section on “Genetic Health Risks” (https://www.23andme.com/test-info/) for the condition “G6PD Deficiency.” However, the DNA sequence data generated by 23andMe includes the information for the other variants. It is just harder to find and interpret.

By making the SNP data available, 23andMe provided a way for this young man and his family to find out that exactly which G6PD deficiency variant they have. This information will help both him and his mother know which medications can cause life-threatening anemia and plan their diets to avoid foods that could also trigger this condition. Surprisingly, the three hematologists consulted about this case had no idea that this genetic information was available through 23andMe.

If you received the gift of DNA testing or one of the many advertised health report services, remember that not understanding the limitations of a report can be dangerous. Most people lack the expertise to delve into the raw data to verify a health report indicating “variant not detected.” Indeed, many consumers may not understand that multiple mutations can cause a condition and that the reports may not include information about all of the possible mutations.

Personal genetic data can be a powerful tool when shared with the right healthcare professionals. It may be beneficial for healthcare providers to start asking if a patient has had DNA testing done through a direct-to-consumer service. If so, the patient can then be referred to a genetic counselor. These experts can help a patient understand the genetic risk reports. Additionally, genetics experts can help identify important information that may not be available in the reports but can be found by looking at the SNP data.

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