Ever expanding genetic carrier testing of infertile couples is becoming excessive
DAVID H. BARAD, MD, MS, is a Senior Scientist and Head of Clinical IVF and Clinical Research at the Center for Human Reproduction (CHR) in NYC.
September 6, 2024, Revised with permission from the June 2024 issue of the CHR VOICE.
BRIEFING: “Testing the Tests” is a series of articles in the CHR VOICE in which Dr. Barad addresses the limitations of popular tests in reproductive medicine. We offer here an edited version of one of his articles, addressing carrier screening for recessively inherited diseases. Decades ago initiated for a handful of high-prevalence conditions, it now, in so-called “expanded” carrier testing, offers tests for hundreds of recessive diseases, with the genetic testing industry arguing that such testing is cost-effective. However, as Dr. Barad suggests, this may be just another new testing habit which may be more motivated by financial considerations of the genetic testing industry than clinical utility.
Carrier screening is used to identify couples who might share recessive mendelian genetic traits that could negatively affect the health of their prospective children if both parents were carriers for the same recessive disease (creating a 25% risk of having a child affected by the disease). Screening for carrier states was first introduced in the 1960s with early efforts exclusively focused on screening of African American couples for sickle cell disease.
In the 1970s, carrier screening was expanded to the Ashkenazi Jewish population after advances in testing methods led to the development of carrier screening programs for Tay-Sachs disease. Further technological progress with the advent of DNA technology in the 1980s allowed for the screening for the CFTR gene for cystic fibrosis (CF), adding by the 1990s for the first time a routinely recommended screening test for the general population in women planning on pregnancy or already pregnant. Both earlier tests had exclusively been recommended only based on racial/ethnic backgrounds of patients. Moreover, in general only the woman was tested, and male partners were tested only if the female proved to be positive as a carrier.
By the early 2000s general (expanded) screening, however, started to include progressively more high-prevalence disorders in the general population, including spinal muscular atrophy (SMA). Recommended maternal testing also for the first time included a condition not inherited as a recessive trait but as a trait passed on through the mother (sex-linked) through a so-called “expansive” gene, the so-called fragile X mental retardation-1 (FMR1) gene (which is located on the X chromosome), and causes the Fragile X syndrome (FXS).
An offspring will have full FXS (when his/her gene has >200 CGG repeats), with males more severely affected than females (who have the potentially compensatory benefit from their second X-gene). If the mother carries between 55-200 CGG repeats (a so-called premutation range) in one of her two FMR1 genes, every one of her offspring has a risk of expanding her premutation to >200 CGG repeats, which would then mean that this offspring is affected by FXS. Because every woman has 2 X chromosomes and only one of them is inherited by every child, the risk of inheriting the one with the premutation – and, therefore, the expansion risk – is, like in a dominant Mendelian inheritance, 50%.
Polymerase chain reaction (PCR) and other new molecular techniques continued to enhance the accuracy and efficiency of all of such screening, while concomitantly reducing the costs. Unsurprisingly, professional organizations, including the American College of Obstetricians and Gynecologists (ACOG) and the American College of Medical Genetics and Genomics (ACMGG) started to support the use of general carrier screening for prenatal/preconception population for common single-gene autosomal recessive disorders, which carry a risk for offspring of demonstrating full phenotypical clinical expression of the disease in 25% of cases if both parents are carriers of the same recessively inherited gene.
The development of next-generation sequencing (NGS) significantly improved the ability to screen for multiple genetic disorders simultaneously. Once again, unsurprisingly, expanded carrier screening panels, therefore, continued to grow, initially involving a few dozens of diseases.
As so often appears the case, commercial laboratories continued adding diseases to routine testing panels with little evidence-based guidance as to which genes did and did not make sense to test for. Yet, the list has continued to grow despite lack of evidence that this kind of “super”-expanded carrier screening, including diseases with progressively lower and lower prevalence, still serves any useful clinical purposes. Nevertheless, such testing has become routine practice in many general Ob/Gyn and infertility clinics, at least to a degree driven by marketing efforts of the genetic testing industry which, of course, cannot deny an obvious profit motive.
But before we get to that, here is a short introduction to the science of genetics to better understand this issue: Even though it is now possible to test for thousands of genetic mutations, it is important to understand that the mere presence of a genetic mutation does not necessarily predict the exact risk such a finding represents for expressing a disease. The reason is that, like a thermostat, mutations can have different degrees of expressions. Moreover, mutations in our genes are very common; they indeed are so common that with routine testing for hundreds of mutations (as routinely is done nowadays), most individuals will test positive as carriers of at least one or two mutations.
And this is where the problem starts: In a large majority of cases, it is still the woman who gets tested first. Since most women will now be found to be carriers for something, most male partners will now also have to be tested (of course, a very attractive proposition for the genetic testing industry). And such partner testing will for legal reasons now have to be performed, even if the prevalence of the female’s mutation in the general population is so low that it statistically equals the probability of winning the lottery.
The likelihood of the male also testing heterozygous-positive for the same genetic trait as the female and, therefore, the risk that this couple may have a one-in-four chance of having an affected offspring, first-and-foremost will, of course, depend on the prevalence of this mutation in the population: the lower the prevalence, the less likely will the male demonstrate the same mutation (though he may have others that don’t matter since the female does not have those).
Assuming the rare likelihood both partners do share a common mutation, further questions then arise as to what to do next, furthermore assuming that the couple does not wish to take the 25% risk of having an affected child with the disease. The parents then, in principle, have two options: The first is to ignore the risk, proceed with conceiving, and test the pregnancy through CVS or amniocentesis to find out whether the pregnancy is affected or not. As noted, the odds are 3:1 that the pregnancy will not be affected. This option, however, requires being comfortable with the notion of terminating the pregnancy in case it proves to be affected.
The second option is a procedure called preimplantation genetic diagnosis for monogenetic diseases (PGT-M), in which the couple undergoes IVF, produces embryos which are tested by PGT-M to see whether an embryo is affected by the disease or not. Under this procedure, only unaffected embryos are transferred, basically guaranteeing an unaffected pregnancy.
This is, however, where the discussion must return to the already previously addressed point that the clinical expression of a monogenic diseases can have variable expression, from very mild to very severe disease. When an embryo is by PGT-M diagnosed as “affected,” it is therefore, in most cases, impossible to know whether the embryos would give rise to a minimally or maximally affected offspring. If a minimally affected embryo is not transferred or is even discarded, that, of course, reduces the cumulative pregnancy chance of the IVF cycle.
An ACOG Committee Opinion, published in 2017 and reaffirmed in 2023, is the last authoritative word on the subject, making the following points:
All patients should be offered carrier screening for cystic fibrosis and spinal muscular atrophy as well as screening for thalassemia and hemoglobinopathies. Fragile X premutation screening is recommended for women with a family history of fragile X-related disorders.
Couples with consanguinity should be offered counseling to discuss their progeny’s increased genetic risks.
Carrier screening panels should be limited to those conditions with a carrier frequency of 1% or greater, have a well-defined phenotype, have detrimental effect on quality of life, cause cognitive or physical impairment and require intervention early in life.
Carrier screening should not include conditions primarily associated with diseases in an adult.
This is, however, exactly why current testing practice appears excessive because most of the conditions screened in large carrier screening panels now offered by the genetic testing industry have a carrier frequency of far less than 1 in 100. Some, indeed, have a carrier frequency of less than 1 in a million, which is the reason for the above-made analogy about winning in the lottery since this means that even if a woman is a carrier for such a rare condition, the chance that her reproductive partner would also be a carrier for the same condition would be less than 1 in a million.
One more point: Some of the conditions screened for in the larger carrier screening panels may be more common, but are obviously not lethal, and only affect quality of life. One such condition is so-called non-syndromic hearing loss, accounting for ca. 70% of all inherited hearing loss cases. The carrier frequency of this condition among couples of European ancestries may be as high as 4% - though- at 2% - it is lower in Asian populations. It, however, is the most prevalent sensory disorder, affecting 1 in 1,000 newborns with hearing impairment. The prevalence of sensorineural hearing loss (SNHL) increases as children grow, reaching 2.7 per 1,000 children by the age of 5.
While hearing loss, of course, affects life to significant degrees, it does not preclude an otherwise healthy and normal life. Couples who are both carriers for SNHL and have only one embryo left after an IVF cycle which, however, by PGT-M was found to be affected by the disease, may, therefore, choose to transfer this embryo after all. As noted before, there is only a 25% risk of having an affected child. The chance of having an unaffected child is three-times better. Parents, therefore, may choose to forgo all genetic testing in such a case and just trust nature in 75% of cases to produce an unaffected child.
Finally, the medical literature demonstrates that many conditions nowadays routinely tested in expanded carrier screening have been reported worldwide in only very few cases. The chance of a partner to also test positive would, therefore, be infinitesimally small (i.e., even smaller than winning in the lottery). The table below demonstrates how small!
What, therefore, is the reason for all this unnecessary testing?
The answer is not an uncommon one in medicine; it is so-called defensive medical practice. In other words, a statistically highly unlikely scenario of being sued for not having tested what could have been tested, represents a very successful marketing tool for the genetic testing industry. The industry, therefore, makes a lot of money with extended carrier testing and the opportunity, indeed, almost doubles if the lady of the house turns out to be a carrier. As noted before, the more diseases we test for, the more women will turn out to be carriers for something, at which time the gentleman of the house must also be tested.
What does all of this cost? The webpage of one company recently made the claim that average “out of pocket” expenses for patients who have met their insurance deductible end up being less than $249. But what if the list price is $5,000 (even if insurance company reimbursements are, of course, greatly discounted) and you have not met any of your deductibles yet? We all know the answer: The patient will get a bill for $5,000 for the testing of one person and for $10,000 if both partners have been tested.
It obviously appears time to be more transparent about this subject and – ultimately – it then should be the patient(s) who decide(s) whether she/they wish to go through super-expanded carrier testing or not. And one more final word: Readers especially interested in ethical issues surrounding prenatal testing should return to these pages on Monday, September 9, 2024 and visit our General Medical News section, where we will offer some thoughts about an interview with one of the leading medical ethicists in reproductive medicine.
Reading List
Reches A, Ofen Glassner V, Goldstein N, Yeshaya J, Delmar G, Portugali E, Hallas T, Weinstein A, Kurolap A, Berkenstadt M, Mantsour T, Abu-Gutstein L, Ries-Levavi L, Reznik-Wolf H, Behar DM, Yaron Y, Pras E, Baris Feldman H. J. Med Genet 2024 May 6:jmg-2023-109629.doi: 10.1136/jmg-2023-109629. Online ahead of print.
Van Tongerloo AJAG, Verdin H, Steyaert W, Coucke PJ, Janssens S. Accepting or declining preconception expanded carrier screening: An exploratory study with 407 couples.
J Genet Couns. 2024 Apr 12. doi: 10.1002/jgc4.1899. Online ahead of print.
Tan L, Qi Y, Zhao P, Cheng L, Yu G, Zhao D, Song YX, Xiang YG. Clinical application value of pre-pregnancy carrier screening in Chinese Han childbearing population. Mol Genet Genomic Med. 2024 Apr;12(4):e2425. doi: 10.1002/mgg3.2425.PMID: 38562051 Free PMC article.