Scientist Stories: Joel Zlotogora, Genetic carrier screening programs for reproductive purposes

So I would like to thank the organizing committee for inviting me. I will present population genetic carrier screening programs for reproductive purposes and, in particular, the Israeli program. When we are giving genetic counseling, usually it's often given to couples after the diagnosis of an affected child. The aim of genetic carrier screening for reproductive purposes is to give the couples at risk informed choices before the birth of an affected child. And when we are speaking about the option of couples at risk, there are several options available. One is to change the marriage plan. Another is to have genetic diagnosis, either prenatal diagnosis and abortion of affected fetus, or preimplantation genetic diagnosis. Do not intervene with the possibility to have diagnosis early after birth, and in some cases treatment. And there are also other options like not to reproduce, gamete donation, or adoption. Screening may be done premaritally, then all the options are available. However, we must be aware of possibility of stigmatization, in particular of the woman in certain population, and if we are doing the fragile X screening, it's maybe a problem. Another possibility is to do preconceptional carrier screening when most of the options are still available, and then the decision is done by the couple and less stigmatization. However, a problem is that many cases it's already— there is already a pregnancy, and then This is the worst scenario in which it's worse for the couple as well for the laboratory. Speaking about population carrier screening, it began with— in the States in the early '70s with the Tay-Sachs and sickle cell programs, both targeted to delineated population in the U.S., African American or Ashkenazi Jews. However, there were several very important differences between the two programs. One is that Tay-Sachs disease among Ashkenazi Jews is always a very severe, lethal disorder, while sickle cell anemia is variable. Ixosaminidase A determination is very good for carrier screening and prenatal diagnosis. But maybe the most important difference between the two programs was that Kebat and collaborators developed the program with the Ashkenazi Jewish community, while the screening for sickle cell anemia was done by public health agencies and governments, and often there were several states in which it was mandatory by law, while Tay-Sachs screening was always voluntary. Therefore, the success of Tay-Sachs screening program led to the acceptance of screening among Jews Ashkenazi Jews and Jews and the Israeli program. On the other hand, the failure of sickle cell screening program was the main reason for the very low slope development of screening for other diseases. When we are speaking about population screening, we can distinguish two types of screening. One is targeted to a founder population like the Ashkenazi Jews, the French-Canadians, and so on. Another is aimed to the whole population. It's mostly about thalassemia, which is very frequent in certain parts of the world due to a selective advantage. There are several types of screening for the whole population. I like to distinguish those who are required by religious authorities, those which are mandatory by law, and those which are voluntary. I will take some example. The screening program in Cyprus is, in order to receive the blessing of the church, it's required a premarital certificate which certifies that the couple was tested and received genetic counseling. However, the decision is left to the couple whether or not to marry. Most of the couples do not cancel the marriage, and in fact, the reduction and the very— it's almost 95% reduction of thalassemia was due to genetic testing. Another example is ultra-Orthodox Jewish community. When Tay-Sachs screening began in the Jewish population. It was done in couple and it was of termination of pregnancy were offered to the couple. Termination of pregnancy is forbidden by the Jewish religion and in Orthodox, very in the ultra-Orthodox community, it was a problem and therefore a special program was designed by the community which took in the particularity of the community, in particular the fact that marriages are by arrangement. Therefore, blood is taken in young individuals in yeshiva or seminary. Each individual receives a number and does not receive the results of the test. The results are kept in the Dor Yesharim database, and when arrangements are made for marriage, they will ask the database whether the numbers are compatible. If both are carriers, there will be another arrangement. If only one is a carrier or both are not carriers, the arrangement will continue for the marriage. In Iran, screening for thalassemia, premarital screening for thalassemia, was made mandatory in 1997, when at the time abortion were forbidden by law. This led to a discussion about religion and abortion, and in fact a new religious rule, fatwa, which allowed termination of pregnancy before 120 days, and therefore this was acceptance of termination of pregnancy was made by law. The law was changed, and then there was a development of prenatal diagnosis and the possibility to have prenatal diagnosis. In parallel, mandatory courses about education for screening were put on. And we can see that there was a very striking reduction of the incidence of thalassemia in Iran, both because of change in marriage plan and the possibility of genetic diagnosis. The third type of program is voluntary. It's done in several parts of the world, but like Sardinia, Sicily, or Israel, as we can see The data from Israel are very nice, very striking reduction of the incidence of thalassemia in Israel. And in fact, I would like to speak more about the Israeli program and first present some particularities of the Israeli population. There are approximately 9 million inhabitants in Israel. Most are Jews. The largest minority are Muslim Arabs, which includes the Bedouin. Small minorities are Christian Arabs and Jews. There are approximately 188,000 live births per year. Many genetic diseases are frequent in Israel, some in all the population, like cystic fibrosis, SMA, or Fragile X. Most of the genetic disease frequent in Israel are found in one population, in the part of this population, for instance, among Jews, according to the origin, Ashkenazi, or the country of origin, among Arabs, according to the religion, and mostly limited to one village or one tribe. When we are speaking about the Israeli Jewish population, the communities were separated one from the other before the creation of the state, geographically very dispersed. On the other hand, they were also separated from the surrounding communities because of marriage within the religion and marriage within the family. In fact, in two surveys performed in Israel among women who gave birth in 1956, 1991, done with similar methods, we can see that consanguinity was very frequent, particularly among Jews who married within their communities outside of Israel or at the beginning of the state. You can see, particularly in Iran, Iraq, and Yemen. However, still, there is a decrease in consanguinity in 1991. Most of the couples were already married in Israel or born in Israel, and this decrease in consanguinity continues. In addition, more and more marriages are between intercommunities among Jews. As a result of the isolation by geographic, religion, consanguinity, many founder mutations are found in the Jewish population. And the Ashkenazi Jews, which is approximately half of the Jewish community, we know for the moment of 222 founder mutations and genetic diseases corresponding. And but also in the other communities are many founder mutations. In the Israeli Arab population, we have a similar situation of isolation. The marriage are within the religious communities, Muslim with Muslim, Christian Arabs with Christian Arabs and Jews among Jews. Very high consanguinity rates. And again, small communities with few founders. We can see from several studies, one of them, that the consanguinity— this is one of them— the consanguinity rates are very high, were very high. Mostly first marriage. Or closer, but there is a reduction in the last years, however, mostly of the very close consanguinity, but it's still very high consanguinity rates. As a result, again, many founder mutations among Muslims, the largest community, but also Jews and Christians. We have genetic database in which all the mutations which are known in Israel are registered, and we can search by ethnic groups, by disease, or by gene. And for the Israeli geneticists, it's also possible with a password to screen, to look according to the village of origin of the patient. As a result, several health programs were developed in Israel. Newborn screenings in the '60s, prenatal diagnosis, and a carrier screening program for reproductive purposes, which I would like to show to you. So in 1980, with the development of Tay-Sachs screening in the States by Kaback and collaborators, it was decided in Israel by the Ministry of Health to organize the screening for Ashkenazi Jews for Tay-Sachs. This was organized and funded by the Ministry of Health. It was done by clinics of the Ministry of Health doing exosaminidase determination, one unique central laboratory. It was done by medical personnel and not by genetic counselors. It was usually It was done by sequential screening. First, the male partner because of change of exosaminase activity during pregnancy and free of charge. In parallel, beta thalassemia screening program began first as a pilot study in the north of Israel and then to the population at risk, both for all the Arab population and for the Jewish population in the communities at risk. In the '90s, many— the molecular basis of many genetic diseases like cystic fibrosis and so on were discovered, and then carrier screening was developed so that at the time, there was a possibility to do the screening through the national program Tay-Sachs and thalassemia, which were free. And in genetic clinics, carrier screening were offered according to the new development, in part reimbursed by complementary insurances. In 2000, it was decided in the Ministry of Health to expand the program to include all the diseases which are severe, frequent, with an incidence of 1 in 15,000, which corresponds to 1 in 60 carrier frequency, and possibility to detect the carrier. However, because of the cost of the program, this was only done progressively and relatively slowly. So in 2002, the first expansion of the program was to include all the diseases which are frequent and which are severe and very frequent, 1 in 1,000. Such a frequency is never found among Jewish, in all the communities of the Jewish communities. It was in fact only for Arabs in small communities, and it was done by genetic counselors within the community, within the village, within the tribes, and completely free of charge again. In 2008, The expansion was to include cystic fibrosis for all the population and dysautonomia for the Ashkenazi Jew. This was the first time that we were able to give screening for all the population. Therefore, it was decided to change the program and not doing it by the Ministry of Health. However, to do the Ministry of Health from this, from 2008, is financing and supervising the program, but the program is done either in genetic clinics or in the clinics of the HMO. It's done mostly by medical personnel, sometimes in the genetic clinics with genetic counselors. In families with a known or possible genetic disease will be referred for genetic counseling. All the other families without any history will give— will receive explanation about all the existing tests, those who are in the program and free of charge, those which are recommended frequent and severe but still because of money problems not in the program, and then also explanation about all the possibility to do very rare or very less severe diseases, but then according to genetic counseling. Again, the program is voluntary. However, it's required by the person responsible for the pregnancy to speak about the program, to recommend the possibility to have the screening, Again, we know that approximately 65,000 individuals are screened each year, and we think that this represents almost all the population or a great part of the population since, again, there are approximately 200,000 pregnancies per year, and it's done once in a pregnancy, and every woman has in mean of 3 pregnancies. The screening is done sequentially. Usually the first examined is a woman because we are doing the Fragile X, and Fragile X is done only in women. If an individual is found to be a carrier, then the significance is explained by a genetic counselor, and the partner is tested. If both partners are carriers, they will receive genetic counseling about all their options, and I would like to emphasize that all the screening is free of charge, and all the options, including PGD, are free of charge in Israel. So they have really all the options offered and free of charge. I would like to show you the result for cystic fibrosis, and we can see several steps, in fact. First, offering prenatal diagnosis for couples who had an affected child. Then the introduction, progressive introduction of screening for cystic fibrosis, first among Ashkenazi Jews and then for all the population. The recommendation of the Association for Geneticists to screen all the population. And then the inclusion of the cystic fibrosis screening in free of charge for all the population. In 2013, all the diseases recommended by the Israeli Association for Medical Geneticists were introduced to the program. Again, all the severe disease, frequent, and that we are able to detect, free of charge and updated every year. So the program since then includes for all the population cystic fibrosis, SMA, and Fragile X. In addition, according to the origin of the couple, program which is targeted for the Jews according to the origin, again, Ashkenazi and different origin, Morocco, Yemen, and so on, For instance, among the Ashkenazi Jews, they will, will command cystic fibrosis, SMA, Fragile X, Tay-Sachs, dysautonomia, Canavan, Smith-Lemli-Opix, Walker-Barbour, and hyperinsulinemic hypoglycemia, and so on. The Muslim population, again, cystic fibrosis, SMA, Fragile X, thalassemia, And then some diseases like Norman Pick Type A in the center and the north of Israel, but mostly according to village. You see one by number. This is a village near Jerusalem, 4 additional diseases. This is a village in the north of Israel, 1 disease, and so on. So we have 41 different villages with different screening. Again, for the Bedouin in the Negev, certain diseases for all the tribes. So most of the disease according to the tribe. I will not go disease by disease because it's too much. Again, Christian Arabs and the Jews, the same, a very large group of disease. That means mainly concerned about this problem this type of program of population screening, and I would like to show you our results comparing to this concern. One is routinization, and we have seen that, in fact, the tests are not done as part of the routine test of pregnancy or following of pregnancy. They are done in separate centers. And in fact, in the Jewish population, as I've shown you, there are two possibilities to choose. One is the Dor Yeshaim program. The other is a general screening, either in genetic clinic or HMO, when it's possible to do it premaritally, preconceptionally, or during pregnancy. For the Arab population, again, for all the population like the Jewish population, in addition, some of the genetic centers are doing screening within the community, within the village. Stigmatization. It's true that we are doing the screening according to religion, to the origin. However, we are not doing screening because you are Ashkenazi or because you are Christian Arab. We are doing screening for all the population. The difference, which tests we are doing are according to the origin. So It's not stigmatizing because we are saying everybody should do the screening. We are— the differences are only for the test. We have an experience that we have seen of almost 40 years for the Jewish population, 15 years for the Arab population, and we didn't see any problem of stigmatization. I must say that the problem is with the 5G LX In particular, Fragile X as a premarital screening, we do not recommend it, and it's not included in the Dor Yesharim because of the implication of the woman who is a carrier is at risk, and it's not depending upon who she will marry. And a third question is, is the state involved with such a program? The agenda is, in fact, to the disappearance of the disease. And I would like to take two examples. One is thalassemia, as we have seen, reduction of thalassemia, but still children are born with thalassemia. And if we look at children with thalassemia, there are approximately 5 or 10 children per year born with thalassemia. We can see that in most of the cases, In some years, all the cases, the parents knew before the birth of the child that they were carriers. And in fact, most of them knew before the pregnancy, so they had all the options and decided to take the risk for an affected child. Some of the cases are diagnosed during pregnancy, and then, in fact, they knew, but we have to remember that Our population is mostly traditional population. It's a problem of diagnostic during pregnancy because the only option is to continue the pregnancy or terminate the pregnancy, and for a large part of the population, termination is not an option, and therefore it's not a true choice. So we need to have most, like this year, that all or most of the cases will be diagnosed before the pregnancy. Another example is An example from one of the Jewish villages in the north of Israel, in which it's a Jews-only village with approximately 330 live births per year, very high consanguinity rates. There are 5 genetic diseases which are screened in addition to the general screen. And it's done by the— under the responsibility of the genetic unit in the area Hospital under the responsibility of Professor Tzipora Falick-Zakai, I would like to speak about one of the diseases, cerebrodystonia syndromatosis, or CTX. This is an autosomal recessive disease, progressive, severe, due to mutation in sterol-27-hydroxylase. Estimate of the incidence in the world is approximately 1 in 2,200,000 live births. In the village, it's 1 in 500 due to a founder mutation which is unique to this village. It should be stressed that there is a known treatment. It was known for years for this disease. During a survey of the disease at the time when molecular diagnosis was done, We have— there were 10 patients, and the most severe manifestation of the disease are dementia and neurological symptoms. And you can see that early on, 2 years, age of 2, age of 7, there is no dementia, no neurological symptoms. And progressively, at the age of 30, already very severe dementia and very severe neurological development. So the screening began in 2003. Already 2,419 individuals have been screened. Carrier rate of 1 in 7, which is expected. It corresponds to the frequency of the disease. At the beginning, couples were discovered during pregnancy at prenatal diagnosis. However, this is a very traditional society. Religious society, and they decided not to interrupt the pregnancy. There were 3 affected pregnancies. They decided not to interrupt pregnancy. The children were born. It was— they received at the age of 1 month treatment, and in fact, it appeared that if treatment is given very early, it's very effective, and the children are developing normally. And therefore, since then, The screening is used to detect couples at risk and to diagnose the infant after birth. Should know that CTX is still not in newborn screening because there are technical problems to, and it's a very difficult test, and Professor Tibora Falick-Zakai and collaborator are developing a test using mass tandem for screening for the population, but for the time being, it's not possible to do it. So concerning the agenda of reducing the frequency of the disease, this is not the agenda of screening program. The agenda is to give the option to the couple at risk, and this is most relevant in the recent years because more and more diseases there are available treatment. And for instance, SMA, which is done in the screening, there is option for the couple to decide to take the risk, and in Israel, SMA treatment is given free of charge to affected children. So they have really a choice to decide what they want to do with the screening. So, If we look at the future, and of course, because of new generation sequencing, lower cost, possibility to do genetic variation in many genes, in fact, expanding carrier screening began with private companies and in fact are used privately in many, offered in many companies. And I know that there are several pilot studies which are thinking about introducing, expanding carrier screening for a population screening, and they are in several populations. The question is, or several questions exist, but some of them, and I will not discuss of them, but either to do the screening by non-mutation like in the Israeli population in which We have a database, we know the mutation, and then we can do the screening only by mutation and not by gene sequencing. On the other hand, gene sequencing possibility to detect more mutation, but then more mutations that we don't know the risk. The question of to do sequential screening or couple screening and giving the risk only to the couple the reproductive risk, not telling whether they are carriers or not, but only whether the couple is at risk for a child, an affected child or not. I would like to stress that for me, screening program for reproductive purposes should include only tests for reproductive purposes. They should not include testing for presymptomatic screening, which can be done but in a different context and should be clearly separated from these tests. And again, our program is very targeted. More and more we are speaking about universal tests. It should be emphasized that a population screening needs an educational effort about the importance of early screening, the importance of knowing before the first pregnancy and the option which exists. And again, to be truly a population screening, it should be available, like the Israeli program, available to the population, and all the reproduction options should be free of charge, including treatment and support of affected children. So thank you. I don't have a slide for thank you, but thank you.