Genetics and genomic medicine in Israel

The State of Israel that was declared independent in 1948 is a country that is ~450 km in length and 180 km at its maximum width (Fig. 1). At the end of 2012 there were 7,984,500 inhabitants in Israel among which 5,999,600 (75.1%) were Jews, 1,387,600 (17.4%) Muslim Arabs, 158,400 (2.0%) Christian Arabs, and 131,500 (1.6%) Druzes (Statistical Abstracts of Israel 2013). In 2012, there were 170,940 live births among which 125,409 (73.4%) were Jews, 36,041 (21.1%) Muslim Arabs, 2610 (1.5%) Christian Arabs, and 2371 (1.4%) Druze. Most of the population lives in the coastal area and, in particular, in the Tel Aviv region. The Jewish population is located primarily in cities, whereas the Arab population mostly resides in small towns and villages. The Jewish people originate from the Middle East. After the destruction of the First Temple, part of the community remained in Palestine while another part moved eastward founding the Babylonian Jewry, ancestors of the Iraqi and Iranian Jews. With the rise of the Greco-Roman empires, Jews began to move also westward as far as Spain and Portugal, where a large Jewish community developed in the Middle Ages. Sephardic Jews are descendants of the Jews who were forcibly expelled during the Inquisition in Spain and settled mostly in the countries along the Mediterranean Sea and in the Netherlands and the New World. The major movement of Jews toward Eastern Europe was in the middle Ages to France and Germany. Later on, there were two important waves of migrations of the Ashkenazi Jews in central Europe: the first in 15th to 16th century eastward to Bohemia and eventually to Poland-Lithuania and then from the end of the 18th century back to the west (Germany, Netherlands, England, and USA). The Jewish communities differed in their cultural outlook and way of life, in their spoken language and their traditions. While differences existed between the various regions where the Ashkenazi Jews were living, it is difficult to delineate subgroups among them. On the other hand, other Jewish communities remained geographically separated one from the other and developed as distinct identities. Therefore, the non-Ashkenazi Jews are best delineated as communities according to their country/region of origin. While the non-Ashkenazi communities represented more than 90% of the Jews in the 12th century, because of the size expansion of Ashkenazim, the non-Ashkenazi Jews represented only 10% of the world Jewry in 1930. The total number of Jews, in particular Ashkenazi Jews, was dramatically reduced by the holocaust but today, the estimated number of Jews worldwide is 13–14 millions. In 2012, there were 5,999,600 Jews living in Israel, ~50% were of Ashkenazi origin (Statistical Abstracts of Israel 2013). Consanguineous marriages are allowed in the Jewish religion and they were common in all the communities including the Ashkenazi Jews. In a survey in Israel of Jewish women interviewed after delivery in maternity wards throughout Israel in 1956 soon after the foundation of the State and therefore representing the situation in the countries of origin (Goldschmidt et al. 1960), the consanguinity rate varied from 2.5% among Ashkenazi Jews to 28.7% among Jews from Iraq (Table 1). In a follow-up study performed in 1991 it was demonstrated that intercommunity marriages became common and within each of the communities consanguineous marriages became less frequent (Cohen et al. 2004). The first observations that various genetic diseases are relatively frequent among Jews were made among Ashkenazi Jews in Europe and in the United States probably because of the size of the community and the relative advance in medicine in the countries in which they lived. Soon after the foundation of the state, several Israeli physicians in particular the late Haim Sheba and the late Richard Goodman initiated studies on genetic diseases among the various Jewish communities (Goodman 1979). Since then the molecular basis of most of the disorders relatively frequent among Jews have been elucidated and many of the mutations were identified. Some of the disorders like thalassemia, Familial Mediterranean Fever (FMF), or G6PD deficiency found with a relatively high frequency among some of the Jewish communities are also frequent in the non-Jewish local population. However, these are exceptions and in most cases the high frequency of the genetic diseases is unique to the Jewish community as a result of its religious isolation. In most of the cases a relatively high frequency is found in a single Jewish community due to a unique founder mutation. There are few diseases in which the same mutations are found in several communities either since they were ancient mutations and existed already before the dispersion of the Jews or because of migration form one community to another (Zlotogora et al. 2000). The non-Jewish Israeli citizens include Muslim Arabs, Christian Arabs and Druzes representing 17.4%, 2%, and 1.8% of the Israeli population, respectively. The Bedouin-Arabs, residing mostly in the Negev desert, comprise ~250,000 individuals, representing 15% of the Muslim Arabs in Israel. There are also some smaller ethnic groups in Israel in particular the Circassians, Armenian, and Samaritains. The Arabs and Druze are generally living in villages/tribes which were founded only by a few individuals less than 10 generations ago. There are more than 100 entirely non-Jewish localities in Israel, with 88 having more than 2000 inhabitants. Most of the localities include less than 20,000 inhabitants a few are larger but still almost all with less than 50,000 individuals (Statistical Abstracts of Israel 2013). In most cases the locality includes only one ethnic community but sometimes the population is mixed. A small proportion of the Arab population lives in towns with a Jewish majority. Most of the Bedouins from the north and center are living in similar conditions as the whole Arab population. In the Negev, more than 60% of the Bedouins live in Bedouins townships, most of the remaining resisted sedentarization and urban life. Similarly to the Arab population in the Middle East, consanguineous marriages are frequent among the Israeli Arabs as well as the Druze with a preference for first cousin marriages. In more than 25% of Muslim Arabs and Druze marriages the spouses are first cousins with an additional 20% related in other ways (Vardi-Saliternik et al. 2002). Among the Muslims, consanguineous marriages are the most frequent among the Negev Bedouins (35% of marriages first cousins and 34% related). Consanguinity is less frequent among Christian Arabs (21% of marriages first cousins and 11% related). Many autosomal recessive diseases have been diagnosed among the Israeli Arabs and Druze, with several being relatively frequent in the whole population such as thalassemia, FMF, or deafness (Zlotogora 2010). Other autosomal recessive diseases are rare in the general population but are frequent in one of the communities either in a large kindred, a village, a region, or even in some cases in a whole community. Most of the rare diseases are present in one community only. In most of the diseases found in more than one community, different mutations have been characterized but there are some exceptions, some being ancient mutations (Zlotogora 2010). In order to improve the availability of the existing knowledge about the genetic disorders in the Israeli population and their distribution in the various Israeli groups, the Israeli national genetic database (available at http://server.goldenhelix.org//israeli/), was launched in 2006 (Zlotogora et al. 2007ab). One of the features includes short clinical summaries that are divided into two parts, one for disorders present among Jews and the other for disorders among non-Jews. Another feature of the database includes data on mutations for autosomal recessive diseases and founder dominant or X-linked mutations. It is possible to search the database for mutations by disorder or by population, classified as either Jews or non-Jews. The Jewish population is subdivided as Ashkenazi or according to the country of origin, while the non-Jewish population is subdivided according to religion. Muslim Arabs have been separated in two groups, Muslims (non-Bedouins) and Bedouins. Results are returned in a tabular format, in which the gene and mutation(s) are given in their official nomenclature, accompanied by the allelic and carrier frequencies, where available, and the respective OMIM number, hyperlinked to the corresponding web page. On 1 January 2014 there was a total of 1528 entries, 724 among Jews and 804 in non-Jews. Another feature allows obtaining knowledge about the genetic diseases existing in each of the localities where Arabs and Druze are living. In this part of the database, the monogenic disorders known in each locality are included even if no molecular data are available (1043 entries on 1 January 2014). In order to protect privacy and to ensure anonymity, data access is provided only to geneticists on the basis of a username and password. The search may be done either by locality or by disorder. This feature allows obtaining a list of the disorders known in the locality or the distribution of a disorder in the different communities and among the different localities. Another feature of the database is about the molecular genetic laboratories accredited by the Ministry of Health. The information includes the type of tests that are provided by the laboratory including details about the mutations examined and/or other services such as linkage or sequencing. Results are returned either by laboratory or by test, allowing knowing where a specific genetic test is done in Israel. The purpose of the law is described in its introduction: “to regulate the conducting of genetic testing and the provision of genetic counseling, and to protect the right to privacy of the person subject to such testing in respect of identified genetic information, but without derogating from the quality of the medical treatment, medical and genetic research, the advancement of medicine and the protection of public welfare.” The law defines a “genetic test” as a test performed to determine sequence of human DNA. The law deals with all the aspects of the genetic tests from the genetic testing laboratories, the information that must be given before and after any genetic test and the different individuals who may give genetic counseling in Israel. One of the bases of the law is that genetic tests must be done in laboratories accredited by the Ministry of Health or, in other words, Israeli laboratories; however, the Ministry of Health allows the possibility to perform tests outside the country when necessary after special authorization. Another aspect of the law is the interdiction to conduct in minors either genetic tests for reproductive purposes or presymptomatic tests without immediate implications. In addition to physician medical geneticists and genetic counselors, the law authorizes MDs to give genetic counseling in the field of their specialty. The law also forbids discrimination at work or for insurance on the basis of genetic tests. While Israel was among the first countries in which a genetic law was promulgated, the law needs to be updated and discussions about its revision begun. The major change concerns the definition of genetic tests which is planned to be changed to include all the tests providing genetic information on the individual. The approaches to genetic testing are diverse in the Israeli Jewish population, mainly because of the differences in the degree of religiosity and traditions from the countries of origin. The ultraorthodox community that represents slightly more than 10% of the Israeli Jewish population is a relatively homogeneous group as for the way it uses genetic tests. Strict Judaism permits abortion only in cases where continuing the pregnancy would put the mother's life in serious danger, but each case is considered and decided independently by the family's Rabbi. Therefore, as a rule the ultraorthodox Jews the preference is for premarital genetic testing (Dor Yeshorim) and not participating in pregnancy screening or testing. 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