June 2007
Should you choose a mate based on genetic fitness? Photo: bio.davidson.edu.
Should your choice of spouse be left solely to your heart, or should the choice incorporate some genetic fitness phase? Obviously, if one is to regard marriage (or any other equivalent arrangement such as cohabitation) as a joint decision to share your life with someone you love, incorporating genetic criteria might seem rather troubling, if not inappropriate. But, on the other hand, if you hold the view that the main reason for your union is procreation, then worrying about genetic compatibility and avoiding inheritance of grave genetic diseases becomes a serious consideration.
The landscape
Genetic testing and genetic screening have become part of contemporary medicine and public health initiatives. These terms are usually used interchangeably, but the term “testing” denotes a genetic test done on an individual voluntary basis, while “screening” implies large-scale, public health initiatives. Examples of genetic testing in clinical settings include testing for the presence of BRCA1 and BRCA2 genes, to identify increased risk for breast and ovarian cancer, or prenatal genetic testing for Huntington disease. Examples of public health initiatives in screening programs include newborn genetic screening programs instituted in all states in the United States (these panels of tests range among states from 6 to 50 diseases) and in other developed countries.1,2
The impetus to identifying the genetic cause of a disease or a susceptibility implies, or should imply, the ability to act upon this knowledge:
- providing timely treatment
- avoiding exposure to environmental risks
- influencing reproductive choices
Importantly, we are not dealing here with genetic enhancement but rather avoiding the birth of babies with lethal or severely debilitating diseases.
Screening for a genetic condition should also meet reasonable probability. It doesn’t make much sense to screen for a condition that is likely to occur in one case out of a million, as opposed to testing for a gene that could be carried by one in fifty. Therefore, discussion and decision with respect to a suggested test is highly dependent on the targeted population and its genetic susceptibilities. The subject of large-scale genetic screening, however, brings to mind notorious past precedents in this field, known as eugenics concepts (i.e., cleansing society’s genetic pool of unfit genes). Thus, it is imperative to restrict such programs to lethal or severely debilitating diseases.
Autosomal Recessive Inheritance. Photo: Wikimedia Commons
Another observation relates to the inheritance pattern of a genetic disease: dominant genes will manifest themselves (depending on their penetrance), while the heterozygote carrier state (having two different alleles) of recessive genes is asymptomatic and usually has no significance to the carrier or offspring. Only if both parents are heterozygous for the same ailment is there a 25 percent risk for every pregnancy that their offspring might receive both recessive genes and exhibit the disease. This latter possibility is the thrust for creating premarital genetic screening programs as we show below. X-linked recessive disorders, caused by mutations in genes on the X chromosome, are not amended to premarital genetic screening.
Many countries have been struggling with the proper way to handle genetic information that has no immediate implication, such as a heterozygote carrier state that is identified during newborn screening.1,2 Should the information be revealed to parents? To tested individuals? If not, why not?
What are the options?
In some populations, the likelihood of mating with a person with one’s same faulty recessive gene is quite high. Since being a carrier doesn’t carry any morbidity and is not manifested (i.e., no phenotype), the only material risk to carriers is that they might conceive a child with a partner who shares the same carrier status. If the genetic condition is a lethal one (e.g., Tay-Sachs disease), or seriously debilitating (e.g., Fanconi’s anemia), one might wish to engage in preventive measures. What are the options?
- One could remain in genetic ignorance with respect to his/her own carrier state, as well as the partner’s, and hope that the risk does not materialize.
- One could resort to prenatal testing (e.g., amniocentesis, chorionic villus sampling), with the only true option in case of an affected embryo being an abortion. It should be noted that abortions carry certain risks to the mother (physical as well as psychological), are fraught with moral issues, and in some societies or subpopulations are strictly prohibited.
What should follow from such an analysis is an effort to avoid such conceptions, if possible. It is now possible to examine embryos prior to gestation in a procedure, called pregestational diagnosis (PGD), in which DNA from a cell of the developing pre-embryo is screened, and the pre-embryo is only returned to the mother-to-be’s womb if it doesn’t bear the suspected gene for which it is tested. However, this procedure is still nascent, is expensive and, above all, necessitates in vitro fertilization with its embodied risks (e.g., invasive egg procurement, hyperstimulation syndrome, success rate of less than 20 percent per cycle) and substantial costs.
But what if it would be possible to avoid the problem altogether? One way to do this is by performing premarital genetic testing (PGT) and informing prospective spouses about their carrier status, allowing potential partners who are both carriers of a particular recessive trait the option not to marry or not to procreate if they so wish. Several PGT programs have been instituted around the globe. The two most cited ones are the Dor Yeshorim (DY) program3,4 and the Cyprus thalassemia screening project. Although their means of operation are different, as are their outcomes, these programs share the same goals:
- abolishing particular autosomal recessive diseases through a comprehensive testing program
- targeting a given population in its entirety
- situating in societies where abortions are regarded as highly undesirable
Example 1: Dor Yeshorim
If one is to fully appreciate PGT in the Orthodox Jewish community, some preliminary remarks are needed:
Some recessive genetic diseases such as Tay-Sachs are prevalent among Ashkenazi Jews (those originating from the Western and Eastern Europe diaspora), who make up more than 80 percent of world Jewry and are believed to be descended from about 1,500 Jewish families dating back to the 14th century.
In Jewish communities, secular as well as orthodox, reproduction represents a most significant social and religious obligation. As a result, the utilization of scientific technology in general, and genetics in particular, in the process of procreation is regarded favorably.5 Additionally, as abortions are seriously objectionable in Judaic ethics, a preference for prevention over termination of pregnancy is clear.
DY operates in ultra-orthodox communities, where arranged marriages are the norm.
Lastly, Jewish communities are generally tight-knit social groups, with numerous self-imposed, self-executed institutions (welfare, education, religious).
All of these factors played out in the design and operation of DY’s premarital genetic screening program.6
Established by Rabbi Joseph Ekstein (who lost four children to Tay-Sachs disease), DY operates among ultra-orthodox communities and screens young adolescents for a panel of 10 recessive diseases that are lethal or severely debilitating (Tay-Sachs disease, cystic fibrosis, Gaucher disease type I, Canavan disease, familial dysautonomia, Bloom syndrome, Fanconi anemia, glycogen storage disease type 1a, mucolipidosis type IV, and Niemann-Pick disease type A). Most of these genetic screening takes place in high schools or religious academia (Yeshivot). For most members of Jewish populations outside the ultra-orthodox communities, Tay-Sachs disease screening occurs outside the Dor Yeshorim program and involves prenatal diagnosis of Tay-Sachs disease, followed by selective abortion when the fetus is found to have Tay-Sachs disease.
Generally, individuals consent to be tested, while parental consent is given in cases of underage minors. Each tested individual receives a coded identification (ID) number. When a proposed match is being considered, both individuals’ IDs are checked in the DY database. The only result that the tested individuals receive is either “advisable” or “nonadvisable” for marriage. They do not receive their specific carrier status, neither at the time of the examination nor at the time of a match test. In this way, most carriers never find out what gene they carry and thereby avoid being seen as defective or a damaged good. If marriage is deemed inadvisable, genetic counseling (by phone only) is available to these individuals. Couples can still get married, but the overwhelming majority do not pursue the match and cancel their wedding plans. Fortunately, this carries a light emotional burden, as consulting the DY database transpires very early in the matchmaking. Stigmatization of individuals and their families is avoided by maintaining strict confidentiality in regard to carrier status.
As mentioned, DY has been endorsed by religious community leaders and became a standard prerequisite in ultra-orthodox matchmaking. The results of DY are regarded as a huge success: Since its inception, over 220,000 individuals have been tested, over 500 incompatible couples identified, and virtually no afflicted children were born. Consequently, DY has aimed at increasing its activities, reaching out to other communities within Jewish society (including modern orthodox) and to non-Jewish communities.
PGT is not restricted to Orthodox Jewish communities. Other important projects focusing on a single disease, thalassemia, were instituted in Cyprus, a Mediterranean island, and Iran. A short description of the Cypriot project follows, and the interested reader may find more information with respect to Iran elsewhere.7,8
Example 2: Cyprus thalassemia screening project
Studies in the 1990s estimated 78,000 blood units were needed annually to treat thalassemia in Cyprus. Photo: Toytoy.
The population of Cyprus has a very high ratio of carriers of thalassemia (1 in 7), a group of blood disorders resulting from underproduction of globin proteins. The treatment of afflicted individuals is based on blood transfusion and expensive medication or procedures (bone marrow transplantation). The overall health and pecuniary burden on the Cypriot community was extensive: It was estimated that without intervention, over a period of 40 years, 40 percent of the population would have to become blood donors to meet the expected 78,000 blood units needed annually, consuming resources equal to the entire health budget.9
This fate was averted by a national program of PGT, set in motion in the 1970s with the support of the World Health Organization. Individuals who wish to marry must present documentation of thalassemia screening to obtain a marriage license. Laboratory services and know-how were introduced to meet the needs of this comprehensive project. Upon testing, individuals learn their personal carrier status, although typically at a later stage in the mating process than in DY. As a result, most couples (some 95 percent) do not revoke their marriage plans and resort to prenatal diagnosis (mainly amniocentesis) and abortion of embryos diagnosed with thalassemia. To complement this social transformation, the Orthodox Church of Cyprus has adopted a lenient approach regarding abortion of afflicted embryos, though not without criticism from abroad. Here again, the overall success of the program is impressive, with near zero births of afflicted newborns.10
Will these programs work in the United States and elsewhere?
Prenatal screening is routinely offered in most countries today. This entails the need for selective abortions of embryos with lethal or severely debilitating diseases. Abortions are not risk- or cost-free, and in light of PGT-demonstrated successes, the question arises as to whether PGT can be instituted in other communities, especially in the United States and some Western countries. Indeed, the social, legal, and ethical challenges are not simple:
Most westerners do not engage in matchmaking, and creating a system for secure predating genetic scrutiny, as in the case of DY, would seem to be unacceptable and not feasible. Yet, some point to the growing acceptance of HIV testing as a prerequisite for serious dating in the United States as an example of a possible change of concept.
DY maintains strict confidentiality and limits access to test results even from the tested individual, which is very different from Western ethical paradigms. The former approach is intended to avoid unnecessary life-long knowledge if a recessive carrier doesn’t end up marrying an individual with the same recessive gene.
Importantly, social cohesion is far tighter in communities served by DY and in Cyprus, a key factor to the successful implementation of PGT. DY and the Cyprus programs are contingent on a powerful trust between the constituents and the governance of the project, a feature seemingly missing in the American context (notably, DY is not imposed by a governmental agency but rather by a social compact). Both programs exert a powerful social pressure, which some term “quasi-coercive.” As PGT programs became accepted practices, either by requiring a proof of testing in Cyprus or by the inability to participate in matchmaking in the ultra-orthodox Jewish community, the individual seems to have lost the freedom to choose whether to be tested or not. Such ostensible curtailments of individual freedom are a hard sell in the United States and some other Western countries.
Indeed, PGT may create a new concept of genetic identity. With PGT, individual responsibility with respect to genetic identity may manifest itself in different ways. In Cyprus, individual carriers also bear the burden of knowing their own genetic risk and are expected either to avoid marriage (which doesn’t usually happen) or to have an abortion if necessary. People tested by DY assume only the responsibility to make a genetically responsible decision with regard to their future spouse. They are not informed of their particular carrier status, as it lacks any relevance unless matched with another carrier. This creates what Prainsack and Siegal term “genetic couplehood.”6 This in turn is a stark presentation of a non-individualistic notion of one’s genetic makeup—you are only part of a larger genetic identity. This could be a major leap for Western and American cultures, where accentuated individualism prevails.
In summary, it would be safe to speculate that in the United States and some other Western nations widespread premarital genetic testing is not around the corner. However, one can envision a future genetic inquiry that is evidence-based and focused on population-specific diseases. The transformation to large-scale initiatives, or the creation of a public health initiative, could create substantial resistance. To this end, resolutions with respect to the public’s genetic and health education, data management and protection, and genetic testing are all needed.
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