Join us at the forefront as we talk genetic testing in primary care with Dr Dallas Read, esteemed gynecologist and **the only** medical geneticist at Tufts Medical Center. Topics include: what internists should be comfortable testing for in the office, how and when to refer for screening, what tests to order, how to interpret test results, how to handle direct-to-consumer results or requests, and so much more! For years, the medical community has been talking about the immense potential for genetic testing to guide diagnosis and treatment. But has it realized its full potential? ACP members can visit https://acponline.org/curbsiders to claim free CME-MOC credit for this episode and show notes (goes live 0900 EST).
Coming to you from the Curbsiders, we hope you’ll enjoy this latest episode about the genes you wear, whether you want to put them on or not. Genes, Genes, they’re (maybe) good for your heart. But do patients want to know if they are, or if they aren’t?
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Written and produced by: Nora Taranto MS4
CME questions by: Nora Taranto MS4
Hosts: Stuart Brigham MD, Matthew Watto MD, Nora Taranto MS4
Images and infographics: Beth Garbitelli MS1
Edited by: Matthew Watto MD, Chris Chiu MD
Guest: Dr. Dallas Reed MD
Use the National Society for Genetic Counselors (NSGC) website to find the closest genetics resources to you or your patient. It can be hard to find geneticists in your area (there’s a shortage of geneticists out there). Telemedicine is also an increasingly viable option for genetics evaluations by experts.
Follow up regularly on testing results showing uncertain findings. There is no legislation requiring labs or clinicians to follow up on variants of uncertain significance (VUS) in patients’ genetic testing results on a regular basis, to make sure these variants don’t change to pathologic.
There are guidelines available online about who needs screening, at the NCCN website.
There is currently no clinical utility to recommending patients order direct-to-consumer (DTC) testing. Most of the information is about ancestry, cilantro, and back hair. Geneticists will almost always reorder tests through a clinical genetics lab, even though there is currently one on-the-market FDA-approved DTC test available for disease risk.
Before you order tests, find the closest genetic counselor/resource to brainstorm alongside. They can make sure you’re ordering the right test, and giving the right pre- and post-test counseling.
Patients, if at all possible, should do their homework before coming in. Let them know you will be asking a lot of questions about family and cancer history and they should be prepared to answer as many of these questions as possible. Many patients will show up to the genetic counselor thinking “Oh I’m just getting a blood test.” The appointment is an hour long, and requires a long conversation.
GINA prohibits employers and health insurers from discrimination based on genetic information about enrollees or employees. But it does not prohibit disability or life insurers from this sort of discrimination. And it does not protect members of the military.
Humans have 46, and they contain almost all of our genetic material that makes us who we are (they contain everything except our mitochondrial DNA and a few other -omes, but that’s a different conversation). We get 23 chromosomes from our mother, 23 chromosomes from our father. Our chromosomes sit in the nucleus of the cell, and contain all our genes, and a lot of other DNA sequences that regulate gene expression (when we make proteins, and what proteins we make).
Genes are the protein-coding segments of chromosomes. We have roughly 20,000 genes. Plants have way more, many of them. For each gene, we have 2 copies, one from each parent. Genes are made up of DNA.
Deoxyribonucleic Acid. DNA is the backbone of everything. It is made up of nucleotides: A, C, T, and G, for short, which combine together to make up our genes (which are coded for in protein-coding domains, or exons) and the regulatory domains (or introns, which get spliced out in order to make the proteins). Most DNA is actually intron, not exon. We are only just starting to learn what these intron domains do.
Locations in our DNA in which there is natural variance–people will have either an A or a T, for example. These polymorphisms are normal in the population, and are not mutations that alter gene function. They can be useful in identifying genetic changes that are more prevalent in a population with a disease, though they are not themselves mutations that lead to the disease.
Modifications to DNA that occur through protein interaction with the DNA sequence (often once it has folded into its tertiary structure). One of the most common forms of epigenetic modification is methylation. The classic board example of epigenetics and disease are Prader-Willi, Angelman, Beckwith-Wiedemann syndromes, in which there is epigenetic imprinting on genes and expression of either the paternal or maternal copy only. Testing for these epigenetic changes is not commonplace, though if there is high suspicion for one of the above conditions, special testing can be done. Some history of medicine, for your edification: research on the Irish potato famine has recently shown that epigenetic modifications may have led to changes in BMI of children who were born long after the famine ended.
Ms. Jeanne Sequence is a 40-year-old female who comes in to the primary care office for her annual physical. Ms. Sequence has a history of Hypertension and Diabetes currently well managed on medications. She mentions, in the course of your visit, that her mother has just passed away at the age of 75 after a multi-year battle with breast cancer. She is concerned about her own risk, and her daughter’s risk of cancer, and would like to know whether she should be getting tested for “those BRCA genes.”
The genetic tests that are most common are for single-gene mutations (e.g. Sickle Cell, hemochromatosis, factor V Leiden, von Willebrand’s Disease), cancer predisposition and reproductive carrier screening, with a non-insignificant amount of genetic testing available for pharmacogenomic analysis (looking at how certain enzymes metabolize medications). Primary care physicians and other non-genetic subspecialists may very well handle single gene mutation testing on their own, without necessary referral to a geneticist (though it’s always welcome!). The answer is often a yes or a no, and there is little room for uncertainty. It’s the other types of testing that are often more complicated and may warrant referral to a geneticist.
For the patient with breast cancer in the family: age at diagnosis, any recurrence or second cancer diagnosis (a second diagnosis is more concerning), age at death, any prior genetic testing.
Then, do a very detailed family history. And ask about male breast cancer, and ovarian and uterine cancer, as well as other cancers in the family, and whether any women in the family had their ovaries or uterus removed for another reason, which may be obscuring some of the risk.
Ethnic background can also be important, since the Ashkenazi population has three founder mutations (there are also other founder mutations in BRCA2 in the Portuguese population, as well as others).
There are guidelines available online about who needs screening, at the NCCN website. You can sign up for free and look at recommendations for detection of high risk cancer. There are also other risk calculators that can help with assessing cancer risk (the GAIL risk calculator and Tyrer Cuzick model).
N.B. If there is a family member with cancer still alive, we want to test that patient. If we get a negative result in a person who’s asymptomatic, then we don’t know if it is negative because there wasn’t a genetic risk to inherit and they didn’t inherit it, if there was a genetic inheritance risk that they were at 50% risk for but did not inherit, or if there’s a genetic cause that we didn’t even test for. –Dr. Reed
Talk about what the testing is and the risk of the disease.
For breast cancer: The focus is on BRCA 1 and 2, and the actual risk. For the general female population, the lifetime risk of developing breast cancer is around 12-13% (Howlader et al. 2013). If a woman has a BRCA mutation, then by age 50 that risk is around 50%, and the lifetime risk is above 80% (Kuchenbaecher et al. 2017). There’s also the possibility of second cancer after first diagnosis. Genetic testing in these cases might change management or push towards prophylactic surgery. You also need to talk about ovarian cancer, the risk of which in BRCA carriers can be as high as 50-60%, and for which there is no screening.
Ask them whether they want the testing. Some people won’t. If they do, there are a few key talking points. First, every gene has multiple types of cancers associated with it, and this can be important information for both men and women. BRCA can put men at increased risk for pancreatic cancer, and prostate cancer. Second, there are many different types of tests for a particular cancer, so you need to discuss the different options, and how widely you want to screen.
Lastly, there must be discussion about the types of results that could come back. There are positive results that signify a hereditary increased risk for a particular cancer. There are negative results, which mean that the panel didn’t find any mutations, but there may be caveats to this (i.e. the test may not be testing the right variant, or the population in which the test was validated may not be the right one for you). Dr Reed sometimes screens patients regularly for cancer in the setting of strong family history, even with a negative test result. Additionally, testing may find variants of uncertain significance. These are results that the geneticist should continue to keep track of from year to year (in case new information arises).
It is important not to forget to talk about laws around genetic testing, specifically the Genetic Information Nondiscrimination Act (GINA), enacted in 2008. GINA prohibits employers and health insurers from discrimination (in making eligibility, coverage, underwriting, or premium setting decisions) based on genetic information about enrollees or employees. Genetic information includes family medical history, disease in family members, or information regarding individuals’/family members’ genetic tests. GINA does not apply to (or protect) individuals covered by military insurance or several forms of federal insurance–Federal Employees Health Benefits, the Veterans Health administration, the US Military, or the Indian Health Service (though these programs may have internal policies that restrict/prohibit genetic discrimination). While GINA prohibits employers and health insurers from using genetic information to decide on price/coverage, it does NOT do the same for life insurance or disability insurance. Genetic testing may or may not be present in the medical records you must submit to these companies to get coverage, so something to be aware of in deciding whether or not to get genetic testing that would potentially stay in your medical record. (NHGRI 2017)
These tests look at the chromosomes and overall structure, for large-scale changes: e.g. duplication of a chromosome, translocation of a part of a chromosome, or macro-deletions or truncations. These include Karyotyping (in which you look at chromosomes under the microscope to make sure they’re all there; useful if suspicious for Turner, Klinefelter’s, or Down Syndrome) and Microarray or Array CGH (More common. Used to look for missing or duplicated segments of DNA, for tumor testing, for assessment of genetic causes of developmental delay or autism, and for identification of sub-chromosomal deletions as in DiGeorge syndrome, which is a 22q11.2 microdeletion)
These tests look at a particular part of the genome, usually in search of a mutation in one gene in particular. Useful to assess for single gene disorders, such as sickle cell, hemochromatosis, or breast cancer risk. Focused NGS is used in panel testing for cancer as well (e.g. in breast cancer or colon cancer panels). What exactly is included on it (which genes, how expansive) will vary from lab to lab.
This sequences the whole genome, or whole exome (WGS or WES, respectively). This can look at it all, in search of deletions, duplications, trinucleotide repeats, and more. WGS is only now becoming clinically available, and is still largely used in the research setting.
The timeline on getting results varies with the expansiveness of the testing (from a few days to a few weeks, usually the latter). The majority of the time and money is spent on interpretation by an expert, rather than running the actual lab test itself. –Dr Reed’s Expert Opinion.
Other great resources for learning more about genetic testing options, and the genetic conditions one might test for: Genetics Home Reference and GeneReviews.org (concise summaries about genetic conditions, with some patient education).
Teams for genetic counseling usually involve: genetic counselors (counselors have completed a two-year masters degree including basic science, advocacy, and social work/psychology coursework), and a clinical geneticist (an MD) who sees the patient and oversees the counselors.
A great resource for finding your closest geneticist is the NSGC website, where you can search based on type of counseling or location and find a counselor that does what you’re looking for. Genetics providers are few and far between: for clinical geneticists, boards are every two years, and about 50 or so geneticists take it. There are more genetic counselors, but training programs are small, and many counselors go into research and industry, where the money is better. There is a shortage of geneticists all over the country right now. Telemedicine is also being used increasingly, since genetic evaluations typically do not require a physical exam.
So many reasons. First, genetics is intimidating, and we don’t necessarily learn it super well in medical school. Genetics is becoming more relevant, and the knowledge we are expected to master is changing and expanding rapidly. Second, the testing options are numerous. You can order the “same thing” from many different places, without realizing they may be testing slightly different variants. Trying to decide where to order and what to order can be quite complicated. Third, appointments to do an effective job are long. It’s hard in a short follow-up appointment to get the family and personal history you need and counsel appropriately about why or why not to do genetic testing. This can be time-prohibitive in the primary care setting. Lastly, interpreting the results can be difficult. You may get back clean yes or no results, but there is a real possibility of getting back results that are inconclusive, or finding variants of uncertain significance (VUS or VOUS, see definition above).
When you have a patient coming in with a genetic condition, whatever it may be, look it up (GeneReviews.org is a great resource). These patients have been asked to be the experts on their disease since childhood, so it is helpful to them to have their physician know a little about what they have.
Genetic counselors can be really useful in this because prices change regularly, as does what insurers are covering and not covering. For more common genetic tests, NCCN criteria will dictate coverage, but every insurer has eligibility criteria on their website so you know. Carrier screening is often covered, as it is usually deemed medically necessary. Whether or not there’s an out-of-pocket copay will depend on the insurance. The price of a typical panel will be around $1500. That said, labs will often bring down the price of the test for the patient, and will communicate the cost before test is completed. But even so, the cost is often variable and uncertain.
Important note: Patients with Medicare will not be covered for BRCA 1 and 2 testing unless they have a history personal of cancer.
A VUS is reported when a nucleotide change is different from the “normal population”, but of uncertain consequence/significance. It may be a normal variant in the population, or it may be pathogenic and cause change- or loss-of-function. Often, the VUS found in one person is rare and therefore, the amount of data required to determine its potential pathogenicity takes longer to collect. Furthermore, if you order a test from four different labs, each lab may call it differently, because each lab has a database of different size and content, which determines what can be inferred about pathogenicity. This information about association with disease may or may not be shared publicly.
The geneticist is very helpful in this situation, and will align the genetic results with the clinical picture, in order to decide whether or not the results could fit with a genetic disorder. This requires clinical expertise and more than just the raw data. However, there is nothing currently mandating that labs or physicians communicate when a VUS is re-categorized as benign or pathogenic. These results could easily, in today’s world, be “lost to follow-up”. A minority–but a real number– of VUS results will turn out to be pathogenic, and labs do not necessarily notify patients or physicians about this change. Therefore, it’s essential for regular reassessment of results. Dr Reed tracks these VUS results and reassesses each year. This allows her to determine if there’s been a change in the interpretation of that result based on population studies.
This is an extremely controversial topic, and has been for some time, among geneticists and other medical professionals alike. There is currently no reason to recommend patients get direct-to-consumer tests for clinical decision-making purposes. Most of these companies test for traits, like the consistency of earwax, back hair, or the “cilantro tastes like soap” gene–the clinical value of which is pretty low. There are some labs that give you more health information. But, for the most part, they’re not looking at a single gene mutation, but instead looking at SNPs (single nucleotide polymorphisms) and comparing your genome to other genomes from other people and saying is it more likely than not that you’re at risk for something.
Patients will sometimes bring in DTC results, saying, “this test says I’m at risk for breast cancer”. In fact, for the most part, what the test did was look at SNPs, and compared outcomes of those SNPs to someone else; and said, “if you have this pattern of SNPs you may be at higher risk of cancer”. Clinically, that’s not so useful, since geneticists would still look at family history and then get genetic testing through the lab that looks for well-validated mutations in genes that are known to cause a change in function.
Moreover, the pre and post-test counseling for these companies varies widely, and may be somewhat minimal. This is an essential part of the genetic evaluation, and when people are ordering DTC tests online, they very well may not be engaging with the consent process much, if at all.
There is currently one lab that is FDA-approved to do BRCA 1 and 2 testing. The issue with this is that they’re looking only at the Ashkenazi founder mutations, so if you are not of Ashkenazi origin, this test is not as useful. But patients may look at the results and think they are not at risk of breast cancer because they were negative on the test for this particular variant. That’s not true, and can be dangerous.
After listening to this episode listeners will…
Dr. Reed reports no relevant financial disclosures. The Curbsiders were sponsored by ACP’s MKSAP 18 for this episode.
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