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With the growing awareness of the importance of family history information as well as increasing access to genetic testing, more people are finding out that they may be at risk for a genetic disease. Sometimes, this knowledge comes before that individual is ready to have a baby, but questions about the potential to have children and the future health of those children may be a concern now. Preimplantation genetic testing for monogenic disorders (PGT-M), also previously called preimplantation genetic diagnosis (PGD),  is a technique that can be used along with in vitro fertilization (IVF) to help families who have or are at-risk for a genetic disease have a baby without fear of passing on that disease. The “Be Prepared for PGT” series is specifically tailored for people who may be concerned about a genetic risk but are not quite ready to pursue a pregnancy. In this first post of the series, we explore how candidacy for PGT is determined. 

What does it mean to be “At-Risk”?

It is important to make the distinction between being “at-risk” to develop a genetic condition and “at-risk” for having a child with a genetic condition. Some individuals know they have a genetic condition, having received a diagnosis either due to their clinical symptoms or by undergoing a clinical DNA test. Others may be aware that they are at-risk to develop a genetic condition due to their family history or through the results of at-home genetic testing. PGT can be beneficial to individuals or couples that are at-risk of passing along a genetic condition to a child. For the most part, this includes an individual who has or is at-risk for developing an X-linked or autosomal dominant genetic condition. It would also include a couple where both partners have both been identified as carriers for the same genetic condition. 

Family History Information

If you know or suspect you may have a family history of a genetic condition, it is important to gather as much information as possible. There are several online resources that can help you think through what questions to ask your relatives. Typically, it is helpful to know the age and gender of each person, their symptoms and diagnoses, the age of onset of those symptoms, and who has died and at what age. This information should be gathered for your immediate family members (mother, father, siblings, children) as well as at least two generations removed from you (aunts, uncles, grandparents on both sides). Through an initiative called My Family Health Portrait sponsored by the Centers for Disease Control, you can actually enter your family history information online, print out a pedigree or chart of your family health history, and save the information so you can update it later. If you see a healthcare professional regarding a concern about a genetic condition, it would be helpful to bring this pedigree to the appointment.  

Genetic Testing

Genetic testing may also help determine if you are at-risk for having a child with a genetic condition. There are several categories of genetic testing, each of which provides different types and levels of information. 

Carrier Screening 

Carrier screening is designed to identify people who carry a gene change or mutation for an autosomal recessive or X-linked condition. For autosomal recessive conditions, both parents have to be carriers of the same condition for a pregnancy to be at risk of developing the condition. For X-linked conditions, just the mother has to be a carrier for the pregnancy to be at-risk. Carriers typically do not have symptoms. Additionally, there may be no history of the condition on either side of the family, so it is highly possible that an individual who is a carrier may not know it. 

Carrier screening is commonly offered and covered by insurance early in a pregnancy, although many individuals choose to undergo carrier screening prior to conceiving to better understand the risks to any future pregnancy. Carrier screening is also part of many at-home genetic tests (see below). Expanded carrier screening, which is available to all individuals even without a known family history of a particular condition, can identify one’s carrier status for hundreds of conditions. If you are considering undergoing carrier screening, you may wish to consult with a genetic counselor to help you determine which test is best for you. 

At-Home Genetic Testing

At-home genetic testing, also called “direct-to-consumer (DTC)” testing allows you to send in a saliva sample from home to have your DNA tested. The testing originated as an ancestry test and has now evolved to include the ability to find relatives previously unknown to you, and, most recently, to tell you information about your health. Companies that offer at-home genetic testing for health look for a defined set of gene changes or pathogenic variants in your DNA sample that have been associated with at least some increased risk for certain diseases. Unlike clinical genetic testing, these tests only look for some of the variants associated with disease risk, meaning that a negative result does not mean you do not have an increased genetic risk for that disease. Similarly, each company decides how they categorize their own results, so a “positive” or “increased risk” result may not actually increase your risk for the disease. One study found that up to 40% of positive results received from at-home genetic testing companies were false positives. Given this, if you are concerned about a genetic risk based on the results of an at-home genetic test, those results will need to be confirmed via clinical DNA testing (see below) before you can be considered a candidate for PGT.

Clinical DNA Testing

Considered the gold standard in genetic testing, clinical or medical DNA testing follows stringent guidelines set out by third party bodies that govern laboratory testing. Clinical DNA testing typically assesses all known variants associated with a disease. Results are clearly categorized based on curation of data from well-respected and verified sources. The results of clinical DNA testing are considered “diagnostic,” meaning that it is reasonable to make medical decisions, like pursuing PGT, based on these results. 

A good example that demonstrates the difference between at-home genetic testing and clinical DNA testing is hereditary breast and ovarian cancer (HBOC) syndrome caused by a BRCA1 or BRCA2 mutation. Mutations in these genes can increase the lifetime risk of breast cancer from the general population risk of approximately 12% up to 72% for BRCA1 carriers. As such, knowing if you have a BRCA mutation is of great import, particularly to those with a family history of associated cancers. 23andMe, a popular provider of at-home genetic testing, only looks at three variants in the BRCA1 and 2 genes. A recent study of over 100,000 patients revealed that when only those three variants are analyzed, the test will miss 88% of BRCA1 and 2 carriers. Contrast this with clinical DNA testing which has a >99% detection rate for BRCA 1 and 2 mutations. As such, clinical DNA testing is typically the more appropriate testing choice for individuals with a known family history of breast or ovarian cancer or for those that have been diagnosed with cancer themselves. 

Discussion with a Genetic Counselor 

If you are “at-risk” for having a child with a genetic condition, you may wish to speak with a genetic counselor. A genetic counselor can answer questions about your reproductive options including PGT. While PGT can be performed for the vast majority of genetic conditions, there are a few genes where this testing is not offered for technical or ethical reasons, so it may be important to confirm the availability of PGT for your situation. Additionally, a genetic counselor can tell you if there is other information or testing that may be needed in order to perform PGT so you can plan accordingly. Keep in mind that you can speak with a genetic counselor at any point, even if you are not yet ready to pursue a pregnancy. There are a lot of steps in determining whether or not you are a candidate for PGT and having the guidance of an expert in the field can be invaluable. 

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