It is almost impossible to open a newspaper or magazine these days without seeing articles about various forms of genetic testing. Considering how much genetic testing has “exploded” into medical practice in many, if not most specialty areas, this cannot surprise and, indeed, reflects on the increasing need of the public to understand why all of this is happening. In addition, through direct-to-public marketing by a number of rapidly growing companies (the best known, though not necessarily “the best” being 23andMe), genetic testing has entered the public consciousness via ancestry testing and selective carrier screening for such recessively inherited disorders as BRCA 1/2 mutations, which primarily reflect increased breast and ovarian cancer risks.
Utilization of genetic testing in its various forms has “exploded” because knowledge in genetics has “exploded.” Discovery of the double-helix structure of DNA by James Watson and Francis Crick, and announced on February 28, 1953, was rewarded with, likely, the best-known Nobel Prize in Medicine and Physiology ever awarded. This discovery initiated a plethora of research in genetics that has not receded. There are almost no areas in modern medicine, reproductive medicine included, where genetic testing has not made major inroads and has significantly advanced medical care.
At the same time, the dramatic increase in genetic testing has on a variety of levels caused concerns. Those include concerns about confidentiality of very personal genetic information with significant potential for abuse in employment and insurance discrimination. But serious questions have also arisen about accuracy of genetic testing methods, their statistical validity and interpretation of results. Of special concern are often simplistic interpretation of genetic findings, which, still, fail to recognize the importance of epigenetic controls over genetic function, a problem recently severely criticized in the review of a book on the impact of genes on human behavior in NATURE (2018;561:461-462).
So-called personalized medicine is to a significant degree dependent on genetic testing because individualization of medical treatments is frequently based on presence or absence in patients of specific genetic markers. Since treatment regimens are frequently based on highly specific genetic markers, oncology is a good example; even in oncology some authorities have, however, recently argued that genetic data that underlie some treatments in breast and other cancers have been over-interpreted.
Criticism has been especially harsh when it comes to direct consumer marketing of genetic testing. Concerns expressed here not only include above-noted questions of diagnostic accuracy and interpretation of results by genetic laboratories but also the public’s ability to understand results in their potential clinical relevance without having access to proper genetic counseling.
The rapid expansion of “consumer genetics,” however, has also led to concerns about privacy and confidentiality in ways until recently still quite unimaginable. It is best demonstrated by utilization, without prior court order, of genetic data from companies that offer genetic testing to the public by police investigators. This is, indeed, how they tracked down one of California’s most notorious mass-murderer, decades after he had ended his killing spree. The most remarkable but also most concerning issue in this case was not that this monster was finally caught, but that he was identified because DNA of some of his close relatives was found by investigators in data sets of one of these direct-to-consumer genetic companies. DNA similarities between relatives and the killer (retrieved from one of his victims), then facilitated his arrest.
As we will further discuss below, huge genetic data sets as are being accumulated by companies like 23andMe, therefore, present significant threats to privacy for everybody who submitted bodily specimens to such companies. But, unbeknownst to most people, this threat also exists to that person’s relatives. In addition, the public must also understand that, even though all of these companies charge nominal fees for their tests, their business model is usually not really based on selling genetic tests to the public. Their real business model is the accumulation of huge genetic data sets, which then, with tools of artificial intelligence, can be used to identify genetic markers for diseases and even normal patent characteristics, which would have enormous economic value for diagnostics and drug development. In other words, the business model is quite similar to social network companies, who offer services for free (in this instance discounted) but then make their profits on selling customer information to interested parties. The one fundamental difference, however, is that social network companies mostly sell information about their clients’ habits and general behavior; genetic testing companies will end up selling your genetic information!
In full disclosure, we must note that CHR is at least marginally involved in the genetic testing business. What’s My Fertility is an Internet company partially owned by CHR that allows women to determine in advance their risk of developing premature ovarian aging (POA). This condition, frequently reviewed in these pages, affects worldwide a whooping 10% of all women, independent of race and ethnic background. CHR investigators were awarded a U.S. patent for an algorithm that includes the FMR1 gene, and allows for early diagnosis of POA, a condition nowadays mostly diagnosed in women's mid- to late 30s, when already quite advanced, in most cases requiring IVF treatments for conception.
In following this diagnostic algorithm, women can be classified as (i) not at risk; (ii) at risk; or (iii) already affected by POA. The whole idea behind this program is to find a way to diagnose POA at young enough ages, so that women at risk still have options of having children earlier and, hopefully, without medical help. They then, as an alternative, also have the option of freezing eggs at young ages, when they still offer best pregnancy potential.
CHR and its investigators, otherwise, have no potential competing interests when it comes to genetic testing but CHR does have very definite opinions on the subject, to be shared in the following paragraphs.
In infertility practice genetic testing may involve testing of one or both parents, testing of embryos produced through IVF or both. What kind of testing is indicated depends mostly on past medical histories of both parents and their families.
Genetic testing of parents
Parents may be genetically tested in two distinct ways: (i) Their chromosomes may be evaluated through blood testing (called a karyotype) and (ii) patients are also routinely evaluated for carrier status of recessively inherited single gene diseases.
1) The first kind--testing of chromosomes--is done to make sure patients do not carry a potentially harmful chromosomal abnormality. This is not a routine test that must be done on every couple. Here at CHR, we reserve this test mostly for couples who have a history of repeated pregnancy loss (habitual aborters). In such couples, one of the parents may carry a so-called balanced chromosomal translocation, which can become unbalanced when half of that partner’s chromosome complement merges with the other partner’s half, and the result then are miscarriages.
Getting a karyotype may also be indicated if medical history and/or appearance of one of the partners suggest the possibility of a chromosomal abnormality, like Turner syndrome (XO) or Klinefelter syndrome (XXY). Though such abnormalities are usually present in all cells of the body, they can also be restricted to only some organs, when they are considered to represent mosaicism. For example, Turner syndrome can be overall mosaic (i.e., only a certain percentage of blood cells show mosaicism) or only the ovaries may be affected by mosaic Turner (i.e., ovarian mosaicism). The more cells are affected, the more typical will be the clinical presentation.
2) Couples trying to conceive are, however, routinely investigated for carrier-states of recessively inherited single gene diseases. This is the second type of genetic testing in fertility treatment setting. There are hundreds of those now that can be tested for at very low costs, in a so-called extended preconception carrier screening (EPCS). The numbers of accessible tests are steadily growing and have reached a point where almost every male or female that undergoes such testing is found to be a carrier of at least one or two such diseases.
Carrier testing was not always that all-encompassing; only a few years ago testing for carrier status was much more restricted and, in principle, based on how frequent carrier states were in a given population. For example, it rarely made sense to test Caucasians for sickle cell disease because detection rates were so low. In contrast since detection rates are very high in individuals of African descent, screening was routine in all black patients. Similarly, Tay Sachs disease is, typically, only found in high enough detection rates in Ashkenazi Jewish populations (but not in Sephardic Jews) and to lesser degrees in French-Canadians and Cajun populations. Consequently, historically only these high-risk populations were tested (by so-called EPCS).
With expanded screening becoming increasingly more popular, a variety of problems have arisen: More testing reveals more positive results. Since partner-testing is mandated once one partner is diagnosed (both partners being carriers for the same recessive disease creates a 25% risk of a child from the couple having the disease), many more tests are performed (which the testing companies, of course, very much like). If required genetic counseling is added, costs for such a testing program quickly grow.
The genetic testing industry, therefore, is aggressively promoting ever larger testing panels, even if added genetic diseases have such low detection rates in average populations that their routine testing really does not make much sense. But by packaging these tests into ever larger offerings, they appear like bargains at first glance, when testing of nearly 300 diseases carries a similar price tag to EPCS of, maybe, 5 or 6 really frequently discovered diseases, like cystic fibrosis (the most frequently observed recessive disease in general populations).
Inherited diseases are, however, not always recessive. They can also be dominantly inherited or in a so-called sex-linked fashion. If a condition is dominantly inherited, it means that if one parent carries the genetic mutation for the disease, every child will have a 50% risk of inheriting the disease. Sex-linked diseases affect only male offspring but are inherited exclusively through the mother. Among the most common so-inherited conditions are red-green color blindness and male pattern boldness.
Genetic testing of embryos
Like their parents, embryos can be tested genetically in two distinct ways: For alleged chromosomal abnormalities in embryos a test, called preimplantation genetic screening (PGS), recently renamed preimplantation genetic testing for aneuploidy (PGT-A), is used. Since especially over the last two years we have discussed PGS/PGT-A exhaustively in these pages, we here will not be repetitive and only summarize our ultimate opinion: We consider this test clinically useless, for women with relative small egg and embryo numbers outright harmful to their pregnancy and live birth chances, and a colossal waste of money for all patients who utilize it.
There is one application of chromosomal testing of embryos which is highly accurate and has, therefore, been offered a CHR for many years, and that is the determination of the sex of embryos (XX vs. XY) prior to embryo transfer for gender selection. In contrast to PGS/PGT-A, this test is reliable because every cell in the embryo (with extremely rare exceptions) is either female (XX) or male (XY). Whatever cell is biopsied, therefore, will correctly represent the whole embryo. Because most chromosomal abnormalities at blastocyst-stage, when PGS/PGT-A is now usually performed, are mitotic abnormalities, they are clonal and are found in only a minority of the embryo’s cells (called mosaicism). Such mitotic aneuploidies, as is now well recognized, also frequently self-correct, which usually does not happen for chromosomes that are present in all cells. Indeed, meiotic aneuploidies, therefore, do not self-correct.
Sex selection in the U.S. is legal, though considered ethically questionable by some. In many countries around the world sex selection is not permitted. It is in the U.S. mostly performed for family balancing but is also used in cases of above-noted sex-linked diseases, where only male offspring are affected. By avoiding male pregnancies, only normal or carrier-females will be delivered, with neither expressing the sex-linked condition.
In contrast to most IVF centers, CHR performs sex selection on cleavage-stage (day-3) embryos. Most IVF centers use blastocyst-stage embryos (day 5-7 embryos). The logic behind CHR’s approach is that day-3 embryo biopsies do not require freezing of embryos because by the time results become available, (day-5) embryos can still be transferred fresh. If the test is performed at blastocyst stage, freezing is an absolute must because embryos would, otherwise, hatch in the laboratory while the biopsy is tested. Especially in older patients and women with low functional ovarian reserve, freezing of embryos should be avoided, unless there is no other choice.
Diagnosis of inherited diseases in embryos is also possible. We already noted above that such inherited diseases, if recessively inherited, will show up in 25% of embryos where both parents are carriers and in 50% if the disease is dominantly inherited. Sex-linked disease will only turn up in male offspring of female carriers.
That this is a much more useful test than PGS/PGT-A, is primarily based on the fact that this test is highly accurate (while PSG/PGT-A has a very high false-positive rate). As also noted before, most genetically inherited conditions produce the same genetic mutation in all cells of the body and are, therefore, represented in all cells of the examined embryo. With mosaicism extremely rare, these disease-causing mutations behave similar to meiotic chromosomal abnormalities which, in contrast to more frequent clonal mitotic aneuploidies, also are present in all cells but hardly ever self-correct.
CHR, therefore, strongly encourages the use of genetic testing in embryos for genetic mutations carried by one or both parents, now under new nomenclature called preimplantation genetic testing for monogenic (single-gene) disorders (PGT-M) as well as for preimplantation genetic testing for structural rearrangements (PGT-SR), which relates to diagnosis of above noted balanced translocations and chromosomal deletions/duplications. CHR also offer these services.
Like during fertility evaluations and treatments parents and embryos can be tested, so can during pregnancy, parents and the products of conception be tested. Every parent can be equally well tested chromosomally and/or for inherited single gene diseases before or during earl pregnancy. The only advantage of testing prior to the establishment of pregnancy is that such early testing may allow for prevention of “abnormal” pregnancies, while a diagnosis of an abnormality during pregnancy opens the door to induced terminations of pregnancy. CHR, therefore, strongly recommends pre-pregnancy genetic testing whenever possible.
Genetic testing of the fetus during pregnancy has been available for decades, initially through the concept of amniocentesis and, more recently in addition through chorionic villous sampling (CVS), which allows for earlier diagnosis of genetic abnormalities in pregnancy than amniocentesis. These two standard methods of confirming that pregnancies are genetically normal (whether in chromosomal numbers or in expression of single gene mutations that can cause diseases), however, in recent years have been at least partially usurped by a new format of genetic testing, so-called genomic-based non-invasive prenatal testing (gNIPT). This new testing method is based on discovery of so-called circulating fetal cell-free DNA (ccfDNA) in peripheral blood of early-stage pregnant women.
A recent Cochrane review concluded ccfDNA appears to be sensitive and highly specific for detection in high risk populations of fetal trisomies 21, 18 and 13. In unselected patients currently available data are, however, still too limited to propose gNIPT as a first-line method for diagnosis (Badeau et al., Cochrane Database Syst Rev 2017;11:CD011767). What this suggests is that amniocentesis and/or CVS are still the gold standard that should not be skipped before making important decisions about the fate of a pregnancy. Even more recently, a group of authors, heavily infiltrated by commercial interests, though concluding that gNIPT, if reasonably priced, is potentially cost-effective as a first-line screening test only if the adopted gNIPT demonstrates a low false-positive rate (Kostenko et al., Fetal Diagn Ther 2018; doi: 10.1159/000491750).
The introduction of gNIPT stands in remarkable contrast to the clinical introduction of PGS/PGT-A, with above cited studies demonstrating a clear emphasis on validation of performed tests in defined patient populations and even involving in depth considerations of ethical concerns (Gammon et al., Ethics Med Public Health 2016;2(3):334-342). PGS/PGT-A, in contrast, was introduced in three different itinerations over 20 years of practice, all without even the most minimal attempts at validation, without any concerns about importance of patient populations in which screening tests are assessed in their sensitivity and specificity and, most importantly, without any concern about false-positive rates that have been shown to be enormously high.
This is a part of the October 2018 issue of the CHR VOICE.
Norbert Gleicher, MD, leads CHR’s clinical and research efforts as Medical Director and Chief Scientist. A world-renowned specialist in reproductive endocrinology, Dr. Gleicher has published hundreds of peer-reviewed papers and lectured globally while keeping an active clinical career focused on ovarian aging, immunological issues and other difficult cases of infertility.
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