About the DeltaF508 Mutation
Clicking on the link for more information about the disease, I learned that one in every 3,000 babies born to parents of European ancestry in the U.S. has CF, making it the second most common inherited disorder. It was also interesting to learn that the incidence is lower in African-Americans (1 in 15,000) and Asian-Americans (1 in 30,000).
For newborn screening, a majority of states recommend that all babies be screened for CF at birth by analysis of blood (one or two drops from a heel stick). Depending on the particular state's program, in many instances this screening includes mutation analysis of the CFTR gene. My first question is do we store the result in the baby’s electronic health record? If not, should it be? And why is it that this mutation doesn’t eventually die out?
The MD Perspective section
Here are three clinical facts and guidelines I learned from the MD Perspective section -
1. Being aware of a family history of CF should lead to genetic counseling for couples considering a pregnancy in which the inheritance of CF as well as its range of clinical manifestations is discussed.
2. There are more than 1,500 known mutations in the CF gene, but about 25-30 of these mutations account for 90% of the mutations found in people with CF.
3. It is important to determine the specific CF mutations in all patients with CF, since drugs specific for treatment of particular CF mutations are being developed, making it imperative that clinical researchers know the specific CF gene mutations present in their patients with CF (known as their "CF genotype").
Salty kids in the Middle Ages
The Timeline tab listed 11 dates from the Middle Ages to 1993 with historical milestones around the understanding of CF. I enjoyed the first entry -
People in the Middle Ages have a saying that modern-day scholars take as a reference to cystic fibrosis: "Woe to that child which when kissed on the forehead tastes salty. He is bewitched and soon must die." Centuries before the gene that is mutated in cystic fibrosis would be found, people saw excessively salty sweat as a premonition of sickness, emaciation, and early death.
Genetic Counseling and other Resources
Another genetic testing company called Navigenics includes an hour of genetic counseling in the price of their service. 23andMe does not, but under the Resources tab, one finds a link to the National Society of Genetic Counselors to help you locate a counselor in your area.
Showing My Results to the Public
Back on July 13th we premiered the first of my actual results on this blog. Four days later I was in Denver presenting to over one hundred people attending a conference by the Mountain States Genetics Foundation. Speaking in the 'Experimental Man' slot of the agenda (with an emphasis on ‘mental’), I logged in to my 23andMe report and projected it for all to see. Many in the audience were skeptical of direct-to-consumer genetic testing services. The goal of my presentation was not to change opinions, but rather to have a dialogue on the issue based on a better understanding on what the services are about.
No matter the point of view, I think all found the content of the 23andMe report very interesting. It led to a fun discussion related to whether or not one would want to know this kind of information about themselves. Would our desire be different depending on the disease? Is the report reliable and accurate healthcare education or just entertainment? How might having this information effect patient questions during visits with doctors and genetic counselors?
More Than My Result
Beyond my carrier status for CF, however, is a recent news article about a possible new treatment that is claimed to be the most efficient gene therapy for cystic fibrosis to be found in the last 20 years. The therapy uses a common cold virus to deliver a corrected gene to cystic fibrosis cells that restores normal function to lung tissue. This type of research is exciting to follow.
Perspective from a Certified Genetic Counselor
Introducing Janet Williams
This is the first opportunity that I’ve had to respond to Grant regarding the information he has been provided as part of genomic testing through 23andMe. It is probably not surprising that like Marc, I also expressed skepticism when I first learned about the premise of 23andMe and again when Grant indicated that he went ahead and sent in a sample for analysis. All sorts of counseling nightmares ran through my mind—and all that before I really had any idea about what would be tested or how test results could be communicated. Incredulity did not adequately express my response. I have spent 30 years in the fine art of genetic counseling and this company planned to offer genomic test results regarding the entire genome without meeting or talking with individuals!
Counseling the Report
My first introduction to 23andMe and its representatives came at an annual meeting of the National Society of Genetic Counselors (NSGC). A glimpse of the sample result report was offered and feedback invited. The example report included the Cystic Fibrosis (CF) carrier screening result. I was quite dismayed by what I read. I gave the company representative an earful and I wasn’t the only genetic counselor who did! In that original version of the carrier report, the interpretation unequivocally stated that the tested individual was not a carrier for CF, rather than that the individual is not a carrier for the DeltaF508 mutation. Several weeks after that meeting, when I learned that Grant had done testing, I nervously asked him about his CF result. I was “primed” to tell him what the CF carrier result really meant and why it incorrectly portrayed carrier testing results.
Fortunately, Grant is not a carrier for the DeltaF508 mutation. I was very pleased to find that the wording of the interpretation of the result had changed and that the wording is now much more appropriate for the information disclosed by testing. The results page for Grant now indicates that individuals who are seeking information about carrier status to assess family risk for CF need to use the recommended panel for more complete carrier detection.
Disease Risk Different from Carrier
Overall, the carrier status section is based on testing for known changes in specific genes well characterized to be associated with a specific disease, e.g. the HFE gene and hemochromatosis (a result of higher interest for Grant), BRCA1/2 and hereditary breast and ovarian cancer. For this blog, the specific change we are talking about in this entry is the DeltaF508 mutation in the specific gene known as the cystic fibrosis transmembrane conductance regulator (CFTR) that when present in two copies is associated with the specific disease CF. In the previous discussion of Crohns disease, the emphasis was on SNPs and haplotypes and the risk for disease. In carrier testing for CF the emphasis is on a specific DNA finding.
The DeltaF508 mutation is a specific DNA change in the CFTR gene that results in a non-functioning product (protein) of the gene. Having one gene mutation in the CFTR gene does not result in CF. So a question might be, “why do we even test for a CFTR mutation?” The emphasis for DeltaF508 testing is more about the risk to pass on that specific DNA finding, rather than the risk to develop disease. This is not the case with each of the conditions lumped under the “carrier status” section of the 23andMe report. In the blog, we plan to go through each of the conditions listed on Grant’s report and to discuss the meaning of each test result in relation to being a “carrier”.
Why Carrier Screening for Cystic Fibrosis
Because of the severity of CF, carrier screening is recommended by several professional associations including the American College of Obstetrics and Gynecology, the American College of Medical Genetics, the American Academy of Pediatrics and the American Academy of Family Practice. Recommended screening for CF mutation carriers in people of European Caucasian background consists of a panel of 25 – 30 gene mutations in the CFTR gene, of which DeltaF508 is just one. It is the most common mutation, but just knowing the DeltaF508 carrier status is not truly carrier screening for family risk planning.
Need More Information on What It Means to be a Carrier
The accompanying information about CF provided by 23andME gives a good description about what to expect if you have CF. [That is you are found to have two copies of non-functioning CFTR genes; one of which is often a DeltaF508 gene mutation, but the other could be any of more than 1500 gene mutations.] The information regarding carrier status for CF is fairly spartan. The focus on the disease symptoms of cystic fibrosis is somewhat misplaced. The more common test result will detect carriers and so concentrating information about the disease may not provide the best service.
While test results will detect an individual with two DeltaF508 mutations, the likelihood of someone getting this test (after age 18) and not knowing that they have CF due to the presence of two DeltaF508 mutations is extremely low. Classical CF leads to significant illness with severe symptoms. It is also possible to have a milder form of CF and have one DeltaF508 mutation and another mutation that leads to less severe illness, more often referred to as non-classical or atypical CF. The result most people are likely to have is variant present, i.e. a “carrier” or variant absent, i.e. a “non-carrier”.
In reading Grant’s post, he didn’t really indicate anything about how he felt about being found a “non-carrier” of the DeltaF508 gene mutation. It probably didn’t mean much at all. Grant is a really curious guy and has investigated many aspects of his report, but it may be that those conditions that are low risk or non-risk are just not all that engrossing. Why would Grant pay much attention to the fact that this is just another of the non-carrier conditions? When might one pay closer attention to the presence or absence of any given variant? What would either variant result mean to someone who is planning a pregnancy in the near future? Should you use this test result to seek medical information?
The results section has the opportunity to delve much more deeply into implications of being a carrier of a DeltaF508 mutation. It is a topic covered richly in the published literature because of newborn screening for CF as well as the professional recommendations for carrier screening. Since Grant is not a carrier, that discussion will have to wait for a genetic counseling session.
Screening for the Counselors
I am not naïve to the option about DeltaF508 mutation screening. Sometime in the early 1990s, again at an NSGC meeting, a vendor booth offered the opportunity for genetic counselors to give a sample as a part of a trial of the commercial offer to do testing for CF. At the time, the test was new and no other mutations had been reported in the CFTR gene. Genetic counselors were given the opportunity to be guinea pigs in the test analysis. I don’t recall elaborate pre-test information (though there might have been) and although I didn’t expect to know results, a letter came with my result.
As my photo reveals, I am of the European Caucasian variety of people. It is possible, though there is no family history of CF, that I could carry the CF DeltaF508 mutation—almost 1 in 30 people like me do. I was relieved to know that I do not carry the mutation and I have not forgotten that I do not carry the mutation. I imagine that if I had been found to carry it, that I would be talking with my daughters about CF carrier probabilities and screening options. I don’t carry it, but I am still talking with my adult daughters about CF carrier screening.
When to Talk with Your Healthcare Provider
So if you have a DeltaF508 mutation what does it mean? Should you talk with your health care provider about knowing this? When? I do think it is relevant to discuss this result with your provider, especially if you are planning on having children in the future. The best time to address risk for CF is prior to pregnancy—prior to conception! It does take two to have risk for a baby to have CF and so your testing and your partner’s testing can and should occur prior to pregnancy. This allows for full conversation regarding options and choices around risk for CF. The single mutation test offered through 23andMe is not adequate for these types of discussions. The admonition not to use the results to make medical decisions is good advice. The appropriate testing for carrier status for CF is best determined by a conversation with your OB/GYN or better yet with a genetic counselor.
Grant raised the question, “Why is it that this mutation doesn’t eventually die out?” That is a very interesting discussion about evolutionary concepts involving selective advantage and genetic drift and founder effect. Suffice it to say, we don’t know yet with CF, but when Sickle Anemia carrier status is discussed, we can put forward a little about these population concepts. I’m hoping that is Marc’s topic!!
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