Genetic Testing in Israel: An Overview

I ANRV386-GG10-08 ARI 8 May 2009 16:55 R E V I E W S E C Review in Advance first posted online on May 19, 2009. (Minor changes may still occur before final publication online and in print.) N A D V A N Genetic Testing in Israel: An Overview Annu. Rev. Genomics Hum. Genet. 2009. 10:8.1 8.18 The Annual Review of Genomics and Human Genetics is online at genom.annualreviews.org This article s doi: 10.1146/annurev.genom.030308.111406 Copyright c 2009 by Annual Reviews. All rights reserved 1527-8204/09/0922-0001$20.00 Guy Rosner, 1 Serena Rosner, 1 and Avi Orr-Urtreger 1,2 1 The Genetic Institute, Tel-Aviv Sourasky Medical Center; 2 Sackler Faculty of Medicine, Tel-Aviv University, Tel-Aviv, Israel; email: guyr@tasmc.health.gov.il; serenar@tasmc.health.gov.il; aviorr@tasmc.health.gov.il Key Words Jewish and non-jewish populations, founder mutation, carrier screening, genetic laboratory testing services, prenatal diagnosis Abstract In Israel, genetic screening and testing are widespread and are on the rise. The socialized medical system, the governmental National Program for the Detection and Prevention of Birth Defects, the central registry of genetic disorders, and the availability of medical genetic units influence the extensive utilization of genetic services. Israeli society is a complex one ethnically, religiously, and culturally diverse, comprised of Jews of many ethnic backgrounds, as well as Christian and Moslem Arabs, Druze, and Bedouins. Multiple founder mutations have been documented in these various ethnic populations, often down to the level of specific villages or tribes. Although carrier screening and prenatal diagnostic testing are well established in the general population, the rejection of pregnancy termination by many religious communities often prevents participation in testing. Culturally appropriate genetic programs have been initiated in religious Jewish and non-jewish communities in an attempt to overcome cultural barriers and reduce the frequency of severe genetic diseases nationwide. 8.1

NEMDB: National and Ethnic Mutation Databases INTRODUCTION The past decade has witnessed remarkable progress in the understanding of human genetics and the genetic basis of disease. Currently, more than 2000 diseases are known to be hereditary, and the identification and characterization of disease-causing genes has, in many cases, allowed the development of treatment and prevention programs as well as close surveillance to facilitate early diagnosis in high-risk individuals. Consequently, the demand for testing of disease-related genetic and genomic changes has increased substantially. The spectrum of genetic testing includes diagnostic testing in individuals suspected of having a specific genetic disorder; predictive testing in asymptomatic individuals with a family history of hereditary disease; carrier screening in healthy individuals who have no symptoms of disease, yet a higher risk due to ethnic history; prenatal testing and preimplantation diagnosis to assess the health status of a fetus or an early stage embryo; and newborn genetic screening to allow early intervention in specific congenital disorders. In Israel, genetic screening and testing is widespread. Although Israel is small, both in size and population, Israeli society is a complex one, ethnically, religiously, and culturally diverse. Many groups live in closed genetically isolated communities and have thus preserved their genetic structures, providing an excellent opportunity for genetic research. Specific diseases have been described in distinct populations in Israel, including Ashkenazi and non-ashkenazi Jews, Arabs, Druze, and Bedouins. The identification of population specific disease-causing mutations, beyond their significant contribution to the scientific community, support the rationale for diagnostic, predictive, carrier, and prenatal testing in these populations. Furthermore, religious communities, both Jewish and Moslem, with opposition to pregnancy termination, have created the need for premarital genetic screening as well as preimplantation diagnostic testing. Here, we review the current status and challenges of genetic testing in Israel. POPULATION-SPECIFIC GENETIC DISEASES IN THE DIVERSE ISRAELI SOCIETY According to the 2008 census, Israel s population of 7,282,000 citizens includes 5,499,000 Jews, 1,461,000 Moslem Arabs (including the Bedouins), 322,000 Christians and Druze, and other small populations including Armenians, Circassians, and Lebanese (Central Bureau of Statistics http://www1.cbs.gov.il/reader. Different ethnic groups in this heterogeneous society have a higher risk for specific genetic conditions than the general Israeli population. The high frequency for a specific disorder is attributed to the founder effect, which is seen in populations that have been isolated for religious, cultural, or geographical reasons and have originated from a small group of common ancestors. In such populations, diseaseassociated founder mutations are passed down with greater frequency because any mutations present in the founders become common in the resulting population (13). The National and Ethnic Mutation Databases (NEMDBs) are continuously updated mutation depositories that contain extensive information on the described genetic heterogeneity of an ethnic group or population. The Israeli National Genetic database is an online repository of information about inherited disorders in the Jewish and non-jewish Israeli population (www.goldenhelix.org/israeli). Jews The Jews are an ancient group of people linked by language, religion, and customs, who for more than 2000 years have established communities throughout the Middle East and the Mediterranean basin. Due to major Diasporas (600 700 B.C.E. and 70 A.D.) as well multiple persecutions and expulsions throughout their entire history, the Jewish people became dispersed into various ethnic subgroups. Many of these communities retained their continuity over long periods of time. The Jews are classified according their country of origin before 8.2 Rosner Rosner Orr-Urtreger

their return to Israel. The largest group is the Ashkenazi Jews whose ancestors originated in Central and Eastern Europe (Germany, Poland, Lithuania, and Russia). Sephardic and Oriental Jews, often defined as non-ashkenazi Jews, are an extremely heterogeneous group with ancestors from Morocco, Tunisia, Libya, Spain, Italy, the Balkans, Iran, Iraq, Yemen, and India, with specific disorders that are unique to specific subpopulations in this group (32, 46). The Ashkenazi Jews represent approximately 50% of the Israeli Jewish population. The unique Ashkenazi population has proven extremely valuable for the discovery of genes responsible for rare single-gene diseases. Most Ashkenazi genetic disorders follow an autosomal recessive pattern of inheritance. These disorders, albeit more frequent, are not exclusive to Ashkenazi Jews (13, 32, 46, 70) (Table 1; http://www.health.gov.il/download/pages/ Table 1 Genetic diseases commonly found in Ashkenazi Jews a book jews01 2009.pdf for a more comprehensive list). Ashkenazi Jewish diseases that are lethal in childhood or lead to severe inability include Tay-Sachs, Niemann-Pick type A, Canavan disease, Bloom syndrome, cystic fibrosis, familial dysautonomia, Fanconi anemia and mucolipidosis IV. Gaucher disease is the most common Ashkenazi Jewish autosomal recessive disease. Different mutations in the GBA gene elicit a spectrum of symptoms, ranging from mild disease to severe and lethal phenotypes (9, 13, 18, 25). Homozygotes for the common Ashkenazi GBA N370S mutation are often asymptomatic or have a mild relatively late-onset disease (type I non-neuronopathic Gaucher), challenging the current inclusion of Gaucher disease in Ashkenazi carrier screening programs (discussed below in the section on Carrier Screening). An unequivocal association between GBA mutation Carrier Disease Disease inheritance Gene frequencys Bloom syndrome AR BLM 1/100 Breast/ovarian cancer AD BRCA1, BRCA2 1/100 1/75 Canavan disease AR ASPA 1/60 Congenital deafness AR GJB2, GJB6 1/25 Cystic fibrosis AR CFTR 1/25 Factor XI (PTA) deficiency AR F11 1/12 Familial dysautonomia AR IKBKAP 1/30 Familial hypercholesterolemia AD LDLR 1/69 Familial hyperinsulinism AR SUR 1/125-1/160 Fanconi anemia C AR FACC 1/100 Gaucher disease AR GBA 1/7-1/18 Glycogen Storage Disease type 1a AR G6PC 1/71 Mucolipidosis IV AR MCOLN1 1/110 Niemann-Pick (type A) AR SMPD1 1/90 Nonclassical 21 OH deficiency AR CPY21 1/6 Tay-Sachs AR HEXA 1/25-1/30 Torsion dystonia AD DYT1 1/4000 Usher syndrome AR PCDH15 1/72 a AD, autosomal dominant; AR, autosomal recessive. www.annualreviews.org Genetic Testing in Israel 8.3

FAP: familial adenomatous polyposis HNPCC: hereditary nonpolyposis colorectal cancer carrier status and increased risk for developing adult-onset Parkinson s disease was established in Ashkenazi Jews (18). A significant prevalence of mutations for the Parkinson s disease susceptibility gene LRRK2 was also demonstrated in Ashkenazi Jews (45). Inherited predisposition to cancer has also been studied in the Ashkenazi population, particularly breast/ovarian and colon cancer. Although breast cancer rates do not differ between Ashkenazi Jews and the general population, approximately 2.5% of all Ashkenazi Jews carry one of three founder mutations in BRCA1 or BRCA2 (BRCA1 185delAG, BRCA1 5382insC, or BRCA2 6174delT), imposing a lifetime risk of 50% 80% for breast cancer and 20% 50% for ovarian cancer (1, 36, 52, 60, 61). Recently it was reported that Ashkenazi carriers of BRCA1 or BRCA2 founder mutations had a 2.5-fold increased risk of other cancers compared to those without BRCA1/2 mutations including a 3.9- fold increased risk for colon cancer in BRCA1 carriers, and an 11.9-fold increased risk for lymphoma in BRCA2 carriers (30). Colorectal cancer rates in the Ashkenazi Jewish population are disproportionately high and may be the highest of any ethnic group in the world (38). The lifetime risk of colorectal cancer in Ashkenazi Jews has been estimated at 15% compared to 5% 6% in the general population (16). Mutations in a single gene result in a marked predisposition to colorectal cancer in two distinct syndromes: familial adenomatous polyposis (FAP) caused by mutations in the APC gene, and hereditary nonpolyposis colorectal cancer (HNPCC, Lynch syndrome), caused by mutations in several genes including MSH2, MLH1, PMS1, PMS2, MSH6, TFGBR2, and MLH3 (37). The APC I1307K founder polymorphism is a cancer susceptibility genetic variant, mainly in Ashkenazim, but explains only partially their higher incidence of colorectal carcinoma (53, 54). The hmsh2 1906G>C founder mutation has been described as being pathogenic for Lynch syndrome in the Ashkenazi Jewish population, and is especially associated with early onset disease (17, 23). Oriental Jews are those inhabitants of ancient Israel, who, following the Babylonian conquest, were exiled to the East and settled in Iraq (about 600 700 B.C.E.). Some of them then followed the developing trade routes from Iraq northward to Afghanistan, Kurdistan, and Uzbekistan, eastward to Iran, and southward to Yemen and India. There were also Oriental Jews who remained in the land of Israel, uninterrupted, and are considered the Israeli (Palestinian) branch of the Oriental Jewry (32). Some of the genetic disorders that are prevalent in Oriental Jews include familial Mediterranean fever in Iraqi Jews, alpha-thalassemia in Yemenite Jews and betathalassemia in Jews from Kurdistan (Table 2; http://www.health.gov.il/download/pages/ tablejews012009.pdf for a more comprehensive list). Sephardic Jews are the Oriental Jews who, during the westward expansion of the Greco-Roman Empires, and later the spread of Islamic civilization toward Spain, began migrating westward and formed what is known as the Sephardic (meaning Spanish) Jewry. During the Spanish Inquisition (in the late fifteenth century) these Jews moved eastward and to the south. Some established themselves along the coast of North Africa, while others established flourishing communities in the Balkans, Greece, and Turkey. Some also found refuge in Western Europe, and North and South America (32). Genetic disorders prevalent in Sephardic Jews include familial Mediterranean fever in Jews from Morocco, Libya, and Tunisia; limb girdle muscular dystrophy in Jews from Libya; and ataxia telangiectasia in Jews from Morocco (Table 3; http://www.health.gov.il/download/pages/ tablejews012009.pdf for a more comprehensive list). Arabs and Druze Non-Jewish Israeli citizens include mainly Arabs (either Moslem or Christian) and Druze. About 82.6% of the Arab population in Israel is Moslem (largely Sunni and Shi a denom- 8.4 Rosner Rosner Orr-Urtreger

Table 2 Genetic diseases commonly found in Oriental Jews a Disease Disease Inheritance Gene Carrier frequency Origin beta- thalassemia AR HBB 1/6 Iran, Iraq, Kurdistan Factor VII AR F7 1/40 Iran FMF AR MEFV 1/5-1/7 Iraq, Iran, Armenia, North-African Jews, Ashkenazi G6PD X-linked G6PD 1/4 Iraq IBM AR GNE 1/12 Iran MLD AR ARSA 1/50 Yemen OMD AR, AD PABPN1 1/7 Bukhara PKU AR PHA 1/35 Yemen a AR, autosomal recessive; DJS, Dubin-Johnson syndrome; FMF, familial Mediterranean fever; G6PD, glucose-6- phosphate dehydrogenase deficiency; IBM, inclusion body myopathy; MLD, metachromatic leukodystrophy; OMD, oculopharyngeal muscular dystrophy; PKU, phenylketonuria. inations), around 9% is Christian (mostly Catholics and Orthodox denominations), and another 9% is Druze. Most of the Moslem Arab and Druze populations are rural, living in villages and small towns settled by a small number of founders. A strong tradition of marriage within the family is maintained, with about 45% of the marriages between related spouses, half of whom are first cousins (28). These high rates of consanguinity have resulted in high rates of autosomal recessive diseases in the Arabs of Israel, a major factor in Table 3 Genetic diseases commonly found in Sephardi Jews a the morbidity and mortality of this population. The distribution of genetic disorders among the Arab population is not uniform and is often restricted to specific geographical regions or even a single village (28, 67, 68, 71). A great deal of effort has been dedicated to characterizing disease-causing mutations in distinct Arab populations; these are listed comprehensively at http://www.health.gov.il/download/pages/ non-jews12009.pdf and http://www.health. gov.il/download/pages/tabledruzainisrael 0607.pdf. Disease Disease inheritance Gene Carrier frequency Origin Albinism: oculocutaneous AR TYR 1/30 Morocco AT AR ATM 1/80 Morocco, Tunisia CJD AD PRNP 1/24,000 Libya CTX AR CYP27A1 1/70 Morocco Cystinuria AR SLC7A9 1/25 Libya FMF AR MEFV 1/5-1/7 Libya, Morocco, Tunisia GSD III AR AGL 1/35 Morocco LGMD AR DYSF 1/10 Libya Tay-Sachs AR HEXA 1/110 Morocco 11-β-hydroxylase deficiency AR CYP11B1 1/30-1/128 Morocco a AD, autosomal dominant; AR, autosomal recessive; AT, ataxia telangiectasia; CJD, Creutzfeldt-Jakob disease; CTX, cerebrotendinous xantomatosis; FMF, familial Mediterranean fever; GSD, glycogen storage disease; LGMD, limb girdle muscular dystrophy. www.annualreviews.org Genetic Testing in Israel 8.5

BBS: Bardet-Biedl syndrome Bedouins The Bedouins, who until a generation ago were a nomadic people, now reside in three regions of Israel, the Negev, the Galilee, and in the central region of Israel. The Negev Bedouins are a relatively isolated highly traditional population with a preserved genetic structure due to the high rate of interfamilial marriages. As in Arab and Druze populations, the high rate of consanguinity in isolated Bedouin communities has led to a high incidence of rare genetic diseases. To date, about 40 serious genetic diseases have been identified as having a significantly higher prevalence in this sector than in the general population. Diseases frequent in Bedouins include the extensively studied Bardet-Biedl syndrome (BBS) where founder mutations in three different genes were demonstrated (BBS2, BBS3, and BBS4 ) (11, 55). A comprehensive list of disorders reported in the Bedouin population can be found at http://www.health.gov.il/download/pages/ book bedouin2009.pdf. GENETIC SERVICES IN ISRAEL To better understand the climate of genetic services in Israel, we provide a brief overview of the Israeli health care system, which is for the most part socialized. Responsibility for all health services lies with the Ministry of Health, which prepares legislation and oversees its implementation, controls medical standards nationwide, maintains food and drug quality standards, licenses medical personnel, promotes medical research, evaluates health services, and supervises the planning and construction of hospitals. The Ministry also acts as a public health agency for environmental and preventive medicine. The National Health Insurance Law, in effect since January 1995 (http://www.mfa.gov.il/mfa/mfaarchive/ 1990 1999/1998/7/National%20Health% 20Insurance), provides for a standardized basket of medical services (from here on referred to as basket ). This basket defines a wide range of inpatient and outpatient diagnostic procedures, treatments, medication, and hospitalization for all residents of Israel, and is updated annually. Medical services are supplied primarily by four comprehensive Public Health Funds, which must accept all applicants regardless of age or state of health. The main sources of funding are a mandatory monthly health insurance tax of up to 4.8% of income, collected by the National Insurance Institute, and employer participation in the cost of insurance for their employees. Beyond the basic healthcare services provided by the Public Health Funds, supplementary medical insurance allowing a wider range of medical services is available for an additional fee. Furthermore, private insurance companies also offer health care insurance covering services not offered by the Public Health Funds. The majority of hospitals in Israel are not-forprofit, owned by the Public Health Funds or government. Less commonly, hospitals are privately owned. Almost all of the major hospitals and the three largest Health Funds have Medical Genetic Units, where genetic counseling and testing is performed. The Israeli National Genetic Database provides a comprehensive listing of laboratories providing molecular genetic testing (http://www.goldenhelix.org/ israeli/). Genetic screening and testing programs in Israel serve four major purposes: carrier screening for prevalent AR and X-linked diseases (premarital, preconceptional, or prenatal), prenatal (fetal) diagnosis, diagnostic testing, and predictive testing. In all cases, the impetus for genetic screening and testing is the ability to act upon the outcome, allowing informed decisions regarding surveillance, intervention, and family planning options for the at-risk population. Here we broach both universal issues in genetic testing as well as issues specific to Israeli society with its complex ethnic, religious, and cultural milieu. Carrier Screening Carrier screening can reduce the burden of autosomal recessive genetic disease, especially in 8.6 Rosner Rosner Orr-Urtreger

specific populations known to be at increased risk for particular diseases. Screening programs in Israel include mutations that are relatively frequent (1:15,000 births, which represents a carrier frequency of about 1:60 in autosomal recessive disorders) or less frequent mutations that cause severe untreatable diseases associated with a shortened life expectancy, for which the phenotype-genotype correlation is well understood. Screening is usually performed only when genetic tests are reliable, identifying at least 90% of the carriers for the mutation/s in question. In the 1970s (1978 in Israel), a carrier screening program for the fatal neurodegenerative lysosomal storage disease Tay-Sachs was initiated in Ashkenazi Jews (where the carrier rate is 1:30). The program, initially based on a biochemical test but now based on molecular testing of founder mutations in the HEXA gene, was a great success both in Israel and worldwide, reducing the burden of Tay-Sachs dramatically (29). A high prevalence of Tay- Sachs disease was subsequently recognized in Jews of Moroccan origin and specific molecular defects were identified (a carrier rate of 1:110) (43, 47). Today, Tay-Sachs screening for ethnic appropriate founder mutations is provided free of charge to all Ashkenazi, part-ashkenazi, and North African or part-north African Jews. This service is financed by the Ministry of Health and implemented in hospitals and genetic units of the major Health Funds. Experience with Tay-Sachs screening proves that heightened awareness, carrier screening, and counseling have a dramatic effect on disease incidence. This success has led to the development of carrier screening for additional recessive disorders prevalent in specific sectors of the Israeli population. The incidence of cystic fibrosis (CF) and the frequency of disease-causing mutations vary among different ethnic and geographic populations. These variations are also noted in different Jewish ethnic groups. Approximately 1:25 Ashkenazi Jews carry a mutation in the CFTR gene. Carrier frequencies are similar in Jews from Libya, Greece, and Bulgaria, and much less frequent in Jews from Morocco, Iraq, Iran, and Yemen (33; www.health.gov. il/download/pages/book jews01 2009.pdf). Moreover, in each Jewish ethnic group, the disease is caused by a different repertoire of mutations. Using a panel of 12 CFTR mutations, 99% of CF alleles in Ashkenazi Jewish patients, 91% in Jewish patients of North African origin, and 75% in Jewish patients from Iraq were identified (48). Free screening, based on the Tay-Sachs model, is now available in Israel unrelated to ethnic origin, although the screening is not of utility in ethnic groups where mutations have not been identified ( Jews originating from Yemen, Lebanon, Syria, India, Ethiopia, and some of the non-jewish populations). Similar to the Tay-Sachs and CF models, screening for thalassemia major (betathalassemia) is also provided free of charge to individuals originating from regions where carrier frequencies are high, including Moslem and Christian Arabs, Bedouins, Druze, and Oriental Jews ( Jews of Mediterranean origin, Iran, Iraq, the Asian regions of the former Soviet Union, particularly Kurdistan where the carrier rate is 1:10). Suspicion of carrier status noted in a blood count performed by the primary care provider is followed by hemoglobin electrophoresis and mutation analysis for a definite diagnosis. Finally, screening for familial dysautonomia has recently become available free of charge for all Ashkenazi or part-ashkenazi Jews (where the carrier rate is 1:30). Despite the current state subsidy of only Tay-Sachs, cystic fibrosis, beta-thalassemia and familial dysautonomia screening, Israeli law demands that a prenatal primary care giver inform patients of the available genetic tests relevant to their family or personal history, or their ethnic group, and refer patients to semiprivate screening services for the completion of the genetic screening. Public Health Funds, through their supplementary medical insurance, and also some private insurance often underwrite part of the costs, whereas others are at the expense of the patient. The Israeli Association of Geneticists CF: cystic fibrosis www.annualreviews.org Genetic Testing in Israel 8.7

SMA: spinal muscular atrophy FRAXA: fragile X has recommended guidelines for screening, and, depending on ethnicity, relevant founder mutations are tested. This screening is aimed at detecting couples without a personal or family history of genetic disease, mental retardation, or malformation syndromes who might be at increased risk for the birth of offspring with severe genetic disorders. In addition to Tay-Sachs, CF, beta-thalassemia and familial dysautonomia mentioned above, screening is recommended for Canavan disease for all Ashkenazi Jews (where the carrier rate is 1:60), and spinal muscular atrophy (SMA) and fragile X (FRAXA) for the entire population. Additionally, carrier screening is available (although not formally included in the list of recommended-diseases) for severe diseases with a frequency of about 1:15,000 1:40,000. Patients seeking semiprivate screening must be informed these additional tests, which include Fanconi anemia C, Bloom syndrome, Niemann-Pick disease, mucolipidosis type IV, Usher syndrome, glycogen storage disease type Ia, maple syrup urine disease, and nemaline myopathy in Ashkenazi Jews; Fanconi anemia (type A) and ataxia telangiectasia in North African Jews; megalencephalic leukoencephalopathy with subcortical cysts and dysferlinopathy (LGMD type 2B) in Libyan Jews; metachromatic leukodystrophy in Yemenite or part-yemenite Jews; Costeff optic atrophy disease in Iraqi or part-iraqi Jews and alpha 1 antitrypsin deficiency (A1AT) in all populations (http://www.health.gov.il/download/pages/ genetics inside.pdf) (4, 62). Screening for Gaucher disease carriers has been offered for over a decade, and although the Israeli Association of Geneticists has renounced screening, it is still performed along with the panel of available Ashkenazi genetic tests. The mild nonneuronopathic phenotype generally resulting from the common Ashkenazi mutation GBA N370S, and its successful treatment via enzyme replacement therapy, distinguish this disorder form Tay-Sachs, Canavan, familial dysautonomia, and Niemann-Pick diseases, which involve fatality in infancy or early childhood, or cystic fibrosis, Fanconi anemia and Bloom syndrome, which may lead to death in early or mid-adulthood. It is therefore highly questionable whether the identification of carrier couples, and possibly the subsequent termination of pregnancy, is appropriate for a treatable condition that is not necessarily lethal or even severely disabling. Although strong objection has been voiced regarding large-scale population screening for a treatable disease (8, 31, 66, 74), as long as it continues, Gaucher disease screening must be accompanied by comprehensive genetic counseling. The high frequency of autosomal recessive genetic disorders among Ashkenazi Jews together with the unfavorable views on the interruption of pregnancy, particularly in the Orthodox Jewish community, have given rise to Dor Yesharim, a unique genetic screening program that aims at preventing the transmission of fatal genetic disorders prevalent in the Jewish community. Dor Yesharim, meaning upright generation (also called the Committee for Prevention of Genetic Diseases), is an international, confidential program that screens mainly Orthodox young adults during their high-school years for nine autosomal recessive diseases [Tay-Sachs disease, cystic fibrosis, Canavan disease, familial dysautonomia, Fanconi anemia, Bloom syndrome, mucolipidosis type IV, Niemann-Pick disease, and glycogen storage disease type I (for Jews of Sephardic origin)] before they begin to contemplate marriage. Gaucher disease was recently removed from the panel because of its nonfatal character. Participants are given an identification number, but are not informed of their carrier status. When contemplating a potential marital partner (often arranged by a matchmaker in the Orthodox community), participants can use the system to learn their genetic compatibility with the potential match, and avoid a marriage that may lead to the birth of a child affected with a lethal autosomal recessive disease. The match is considered to be compatible as long as both parties are not carriers of the same recessive trait. Each member of the couple may be a carrier for a different disorder, but that information is not revealed as it does not affect their compatibility 8.8 Rosner Rosner Orr-Urtreger

as a couple. If a prospective couple is found to be genetically incompatible, marriage is discouraged to avoid producing affected offspring (10, 15). Carrier screening is also performed in Israel for diseases with a frequency of about 1:1000 births (which represents a carrier frequency of 1:16 in autosomal recessive disorders). These are diseases generally found in various Arab populations of Israel, often limited to specific villages or geographic regions owing to isolation and high rates of consanguinity (26, 28). Currently, tens of diseases are screened in relevant villages and tribes (Table 4; http://www. health.gov.il/download/forms/a3206 mr34 08.pdf ). Although these diseases represent a major factor in the morbidity and mortality of the Arab population, reducing the incidence of affected offspring is challenged by traditional beliefs and values. Intense health education and culturally appropriate genetic counseling programs have been initiated, and although the complete abandonment of interfamilial marriages is unlikely, increased awareness of the medical consequences of such marriages is apparent. A comprehensive program run by The Genetics Institute of the Soroka Medical Center in Beer Sheba and the Israel Ministry of Health aims to identify the genetic mutations or markers for conditions effecting the Bedouin population and offers free, culturally appropriate genetic screening and counseling services (12). Genetic counselors come from within the community, speak the native language and are sensitive to the traditions and concerns of the population in question. Similar programs have been set up in communities around the country. A carrier screening program has been initiated in an isolated population on the Mediterranean coast, where the proteintruncating CC2D1A G408fsX437 mutation has been associated with severe autosomal recessive mental retardation in a significant percentage of residents. Genetic counseling and testing, provided free of charge, revealed a carrier rate of 1:11 (7). Similarly, a large-scale carrier-screening program for spinal muscular atrophy (SMA) and spinal muscular atrophy with respiratory distress type 1 (SMARD1), major monogenic causes of infant mortality among Arabs in Israel, was successfully established in the same isolated population on the Mediterranean coast (6). Data suggest positive outcomes of educational interventions, with 3660 Israeli Arabs screened for genetic diseases in 2004, compared to 3127 in 2003. Moreover, screening was often sought prior to marriage, suggesting that with further education and perhaps the involvement of community or religious leaders, a more widespread premarital screening for population-specific prevalent mutations might be possible. In all carrier-screening scenarios discussed above (except for Dor Yesharim), disclosure of results must be accompanied by genetic counseling. When a mutation carrier is identified, the spouse is also tested. In specific communities, screening/testing is accompanied by counseling. Counseling includes an explanation of disease risk, disease manifestations, range of severity, and management options. A negative screening test result for one or both partners significantly reduces the possibility of an affected offspring, but does not exclude it because test sensitivity is usually less than 100%; therefore not every carrier is identified. If both parents carry the same mutation, a number of reproductive options are available to prevent the birth of an affected infant, including avoidance of pregnancy, sperm or egg donation from a donor who is a noncarrier, preimplantation genetic diagnosis (PGD) with implantation of only unaffected embryos (discussed below), prenatal diagnosis by DNA testing on chorionic villi or amniocytes to determine fetal status (discussed below). Pregnancy termination might be an option, although it is not accepted in all sectors of Israeli society. Counseling must be guided by medical considerations, but must take into consideration the outlooks and sensitivities of the patient s cultural and religious affiliations. Prenatal (Fetal) Diagnostic Testing Prenatal care in Israel is a universal service mostly provided by gynecologists and SMARD1: spinal muscular atrophy with respiratory distress type 1 PGD: preimplantation genetic diagnosis www.annualreviews.org Genetic Testing in Israel 8.9

Table 4 Carrier screening in Arab communities for diseases with a frequency of about 1:1000 Disorder ACTH deficiency Albinism Ataxia telangiectasia Bardet Biedl syndrome Bartter syndrome Biotinidase deficiency Carni syndrome Cerebrotendinous xanthomatosis Cockayne syndrome Congenital insensivity to pain Congenital myopathy Congenital nephrotic syndrome Cystic fibrosis Cystinuria + Epidermolysis bullosa Glycogen storage disease 1 Hemolytic uremic syndrome Hyperinsulinism Hyperoxaluria Hypomagnesemia Hypoparathyroidism + Krabbe Leber amaurosis Mental retardation Mitochondrial depletion Molybdenum cofactor deficiency Maple syrup disease Nephronophthisis Niemann Pick type C Non ketotic hyperglycinemia Osteopetrosis Pendred syndrome Prolidase deficiency Pseudo rheumatoid dysplasia Puntamen dysgenesis Pycnodysostosis Spinal muscular dystrophy (SMA), spinal muscular dystrophy related disease (SMARD) Tay-Sachs disease Ventricular tachycardia Vitamin D resistant rickets Gush Halav Ivlin-Christians Community Majar; Horfish; Sajor, Bedouin tribe in Southern Israel Mishhad Yarcha Kisra Tuba Zangria in Northern Israel Abu Gosh Bedouins in Southern Israel; Abu Gosh; Jiser Al Zarka in central coast Dir al Asad Abu Gosh; Bukata ; Kmane Jabar Mukbal; Ir Carmel; Zur Bachar Mishhad Jiser Al Zarka in central coast Sajor Boena Nujidat Bedouin tribe; Pke in Elut; Jerusalem area Naim Yarcha Elut Boena Nujidat Jiser Al Zarka in central coast Pke in; Abu Snen and Bedouin tribe Slame; Kmane Sachnin 8.10 Rosner Rosner Orr-Urtreger

mother-and-child health (MCH) care nurses in the community. The National Program for the Detection and Prevention of Birth Defects was established by the Ministry of Health and has been in operation since 1980. It recommends second-trimester maternal serum screening (triple test) between 16 18 weeks of gestation to identify risk of Down syndrome and neural tube defects for all women, and provides free invasive diagnostic tests for women older than 35 years at the beginning of their pregnancies. Additional prenatal tests routinely offered include a first-trimester screening service between 10 13 weeks gestation, which includes ultrasound to determine nuchal translucency and a blood test for free beta- HCG and PAPP-A (63, 64); a fetal body scan between 16 20 weeks gestation, and secondand third-trimester ultrasound scans (www. mfa.gov.il/mfa/mfaarchive/1990 1999/ 1998/7/National%20Health%20Insurance). If first- or second-trimester screening tests indicate a risk of more than 1:380 of having a child with Down syndrome, neural tube defect, chromosomal abnormality, or a molecularly defined genetic disease, invasive diagnostic tests (chorionic villus sampling or amniocentesis) are offered free of charge. Invasive diagnostic testing is also given free by the state to women with a high risk of an affected fetus as determined in genetic counseling, including a known genetic disorder in the family, two parents carrying mutations for the same autosomal recessive disorder, a previous pregnancy with a chromosomal anomaly, a known chromosomal anomaly in one of the partners, a combination of specific malformations on ultrasound, exposure to teratogenic medication, or an infectious disease before or during pregnancy. Invasive diagnostic procedures show a trend of increase from 2002 2007. In 2007, the primary indications for prenatal testing were a combination of specific malformations on ultrasound and abnormal nuchal translucency, whereas among the monogenic disorders, carrier state for FRAXA was by far the main reason for testing. Prenatal testing in cases with abnormal nuchal translucency revealed mainly trisomy 21, as well as additional chromosomal abnormalities such as trisomy18, Turner, trisomy13, Klinefelter, and triploidy ( J. Zlotogora, personal communication). Despite the National Program for the Detection and Prevention of Birth Defects and the use of chromosomal studies for Down syndrome in about 20% of pregnant Israeli Jewish women (59), more than 50% of Down syndrome cases in Israel are born alive (72). The influences of religious, traditional, cultural, and socioeconomic factors on these data have been studied extensively (21, 57, 58). A recent study suggested that the high percentage of Down syndrome infants is related to the informed choices of the mothers and not failure of the national preventative program. Utilization rates of prenatal diagnosis in women older than 35 years at the beginning of their pregnancies were 57.8%, 52.1%, 15%, and 16.3% in Christians, Jews, Moslems, and Druze, respectively. In women where previous Down syndrome pregnancies were terminated, the majority opted for prenatal diagnosis in subsequent pregnancies, whereas women who had given birth to a child with Down syndrome mainly chose not to utilize prenatal diagnosis in subsequent pregnancies. Most Down syndrome babies were born in religious communities, both Jewish and Moslem. In religious/traditional Jewish communities 95% of the cases diagnosed with Down syndrome are born alive, compared to 25% in largely secular communities. The rates of prenatal diagnosis utilization and Down syndrome interruptions in various communities, 52% for Jews and 18% for Moslem Arabs, highlighted the correlation between objection to pregnancy termination and rejection of what is therefore perceived to be superfluous diagnostic testing (72). A survey of awareness and acceptance of prenatal diagnosis and termination of pregnancy in the case of a severely affected fetus in Arab Moslem women revealed a low level of awareness of genetic risks, disbelief in the accuracy of genetic testing, and high level of opposition to pregnancy termination. These www.annualreviews.org Genetic Testing in Israel 8.11

views were more frequent in women who were less educated or of lower socioeconomic status. When given an explanation about prenatal diagnosis, most women said that they would agree (27). Additional studies summarized that being secular, having a higher income, fewer children, and being of Ashkenazi origin remained significant factors in determining performance of prenatal testing (42, 51). Although beliefs and values in many religious communities often prevent participation in prenatal testing, prenatal testing and termination of affected pregnancies remain the means of prevention of Down syndrome and other genetic diseases. According to Jewish law, abortion is forbidden after 40 days of conception, whereas in Islamic law if elective abortion is permitted due to a fetus affected with a severe condition this must be before the 120th day of the pregnancy (24, 27). The development of prenatal testing programs sensitive to the needs of specific communities, such as firsttrimester prenatal testing that would allow the interruption of a pregnancy early in gestation (27, 50, 56, 69, 73), together with the endorsement of religious and community leaders, might well modify culturally related attitudes and perceptions, thereby reducing the frequency of severe genetic diseases in Israel. Preimplantation genetic diagnosis (PGD) followed by implantation of unaffected embryos offers high-risk couples the option to decrease the risk of genetic disease in their offspring, without the dilemma of a prenatal diagnosis that may be followed by a pregnancy termination. In Israeli society, which places great emphasis on reproduction, yet in many sectors rejects the termination of pregnancy, PGD is most valuable. General guidelines for PGD practice in Israel were published by the Israeli Ministry of Health in 2006. The main categories for PGD referral in Israel include these conditions: both parents are carriers for the same monogenic disorder, one parent is a carrier of a balanced translocation with a high risk of having offspring with the same translocation, one parent is a carrier of a dominant or X-linked mutation that can lead to a severe disease, and sex selection when one parent is a carrier of X-linked disease (such as Duchenne muscular dystrophy). PGD in Israel involves the cooperation of a genetic institute with an in-vitro fertilization (IVF) unit and a diagnostic molecular and cytogenetic PGD laboratory, and is currently performed in several major hospitals (2, 3, 39 41, 65). Genetic Diagnostic Testing Diagnostic genetic testing is carried out in symptomatic individuals, primarily in infants and children suspected of mental retardation, malformation syndromes or familial/hereditary disorders, and in oncology patients. In the case of a child with congenital malformation or developmental delay, generally the neonatologist, pediatrician, or developmental neurologist refers the child for testing. In addition to consultation with a geneticist, the basket of medical services in Israel covers a basic repertoire of genetic and biochemical tests, including chromosomal analysis, testing for fragile X syndrome, FISH analysis for specific microdeletion syndromes (such as Di Georgevelocardiofacial and Williams syndromes), testing for Duchenne/Becker muscular dystrophy, spinal-muscular atrophy, and spino-cerebellar ataxias, as well as biochemical tests for tens of disorders including glycogen storage diseases, lysosomal storage diseases, lipid disorders, mitochondrial disorders, and endocrine, hematological, and miscellaneous disorders (http:// www.health.gov.il/download/genetics/2.doc). Many other genetic tests available outside of Israel are not included in the basket. These tests, such as CGH-microarray analysis (5) and other diagnostic tests aimed to detect mutations in specific genes, are often recommended to patients as part of the genetic diagnostic work-up. However, since most of these tests are expensive and are paid for out-of-pocket by the patient, they are not routinely pursued. In the oncogenetic setup, diagnostic testing is mainly performed in the cases 8.12 Rosner Rosner Orr-Urtreger

of breast/ovarian cancers and of familial/ hereditary colon cancer. Testing for known mutations in BRCA1 and BRCA2 [the three common Ashkenazi mutations: BRCA1 185delAG, BRCA1 5382insC, BRCA2 6174delT; the Yemenite founder mutation BRCA2 8765delAG (35); the Iranian/ Iraqi mutation BRCA1 3053T>G (49)] is provided by the basket for cancer patients belonging to an ethnic group where the carrier rate for known BRCA1 and BRCA2 mutations is > = 1%, and the patient has ovarian cancer; the patient has breast cancer diagnosed before age 50 years; breast cancer is bilateral; a male patient has breast cancer; breast cancer at any age when at least two relatives have been diagnosed with breast or ovarian cancer (one a first-degree relative and one either first- or second-degree relative) (http://www. health.gov.il/download/forms/a2494 mr12 2004.pdf). Genetic counseling is usually initiated prior to genetic testing and provided again with the disclosure of results. Surveillance programs as well as options such as chemoprevention, prophylactic bilateral oophorectomy, and/or mastectomy as well as the limitations of these preventive strategies are discussed with the patient. Recently, breast MRI has become available in the basket as a routine preventive measure for all women carriers of BRCA1 or BRCA2 mutations. No formal guidelines exist regarding diagnostic testing in colon cancer, although due to heightened awareness on the part of family physicians, gastroenterologists, surgeons and oncologists, colon cancer patients or those suspected of harboring familial syndromes are often referred for genetic counseling. The molecular analysis of the APC gene is currently referred to a single center in Israel (19) and if no mutation is found, further molecular analyses are recommended including the two common recessive MYH hotspot mutations and multiplex ligation-dependent probe amplification (MLPA) in cases suspected of having APC deletions. Cases fulfilling the revised Bethesda and/or Amsterdam criteria for Lynch syndrome are referred for Microsatellite Instability (MSI) testing, followed by sequencing of hmsh2, hmlh1 and hmsh6 (22). A recent Israeli study identified a significant percentage of gynecological cancers, particularly endometrial cancer, in Lynch syndrome families carrying the Ashkenazi hmsh2 1906G>C founder mutation. The authors suggest that Ashkenazi women diagnosed with endometrial cancer should be referred for genetic counseling and testing for the hmsh2 founder mutation (1906G>C), especially if the cancer is detected before the age of 70 years in women with a personal or family history of colorectal cancer (34). Predictive Testing Predictive testing is offered to asymptomatic individuals with a family history of a genetic disorder (or an identified mutation) and is indicated if early diagnosis allows interventions that reduce morbidity or mortality, or if diagnosis influences reproductive planning. In Israel predictive testing is in clinical use for asymptomatic members of families with severe or lethal autosomal recessive disorders, autosomal dominant disorders such as Huntington disease (14, 20), or X-linked diseases such as Duchenne muscular dystrophy and Emery-Dreifuss muscular dystrophy (44). Healthy individuals with a first- or seconddegree relative diagnosed with breast or ovarian cancer who tested positive for a mutation in either BRCA1 or BRCA2 are also entitled to predictive genetic testing (in the basket ). Testing relatives at risk for other familial cancer syndromes, such as familial adenomatous polyposis and retinoblastoma, is also recommended, particularly for reproductive and preventative considerations. As in diagnostic testing, genetic counseling is mandatory and is initiated prior to genetic testing and provided again with the disclosure of results. In the case of cancer predisposition genes, predictive testing often allows opportunities for intense surveillance, early detection, MLPA: multiplex ligation-dependent probe amplification MSI: Microsatellite Instability www.annualreviews.org Genetic Testing in Israel 8.13

timely treatment, and possibly lifestyle changes or prophylactic intervention to prevent disease. However, predictive tests deal in probabilities, not certainties, since variable expressivity and penetrance, inconsistent genotype-phenotype correlation, and modification of predisposition genes by the interplay of multiple genetic and environmental events all influence disease manifestation. In the case of breast cancer, predictive tests identify only a small proportion of the people who will develop disease as most cases are not inherited, despite having an affected relative. Therefore, although a negative result can create a tremendous sense of relief, disease risk is not eliminated, but rather reduced to that of the general population. These uncertainties emphasize the importance of genetic counseling, where the possible benefits of screening like risk reduction must be weighed against consequences such as difficult reproductive choices and implications regarding other family members who might also be at increased risk for the same mutation. FUTURE ISSUES Legislation Concerning Genetic Testing The Genetic Information Law was passed by the legislative branch of the Israeli government on December 2000. The purpose of this Law is 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 bars employers from using individuals genetic information when making hiring, firing, job placement, or promotion decisions and prohibits health insurers from denying coverage to a healthy individual, or charging that person higher premiums, based on a genetic predisposition to developing a disease in the future (http://www.jewishvirtuallibrary.org/ jsource/health/geneticinformationlaw. pdf ). 1. As emphasized in this review, the Israelis are in large eager consumers of genetic services. Advances in genetic diagnostic technology will provide greater opportunities for genetic testing. For example, CGH array, now in routine use for clinical genetic diagnosis in pediatrics, will likely be offered in prenatal/fetal screening as well. We expect that this modality will cause an increase in prenatal testing (amniocentesis or CVS) in order to screen for an ideal baby and will raise serious ethical questions regarding the excessive use of genetic testing during the prenatal phase. 2. In these challenging economic times it seems unlikely that costly genetic tests such as complete sequencing of candidate disease-causing genes and CGH arrays will be included in the basket, suggesting that advanced genetic tests will be restricted to the privileged. 3. The use of preimplantation genetic diagnosis is provided now in the basket in certain instances and is expected to rise significantly. As growing numbers of individuals undergo genetic screening, many Israeli couples will be defined as high-risk carriers for AR or X-linked diseases. Will this cause an epidemic in the use of PGD? Who will cover the cost, and how will it affect Israeli medicine? 4. How will personal genomics companies, which disclose a spectrum of genetic information from health risks and eye color to food preference and athletic ability, influence consumerism among the Israeli population, eager for genetic information that is not directly related to health? How will this information influence prenatal decisions? 8.14 Rosner Rosner Orr-Urtreger

5. How will the detection of mutations in genes causing adult-onset diseases such as cancer and neurodegenerative disorders influence prenatal testing and embryo selection? 6. Lawsuits against genetic services are on the rise. Recently, a record high compensation (14 million New Israeli shekels or about $US 3.5 million) was awarded to a child with a genetic disorder and this verdict will surely encourage similar lawsuits. How will this climate affect the genetic workforce? Will physicians and genetic counselors reconsider professional affiliations? DISCLOSURE STATEMENT The authors are not aware of any affiliations, memberships, funding, or financial holdings that might be perceived as affecting the objectivity of this review. LITERATURE CITED 1. Abeliovich D, Kaduri L, Lerer I, Weinberg N, Amir G, et al. 1997. The founder mutations 185delAG and 5382insC in BRCA1 and 6174delT in BRCA2 appear in 60% of ovarian cancer and 30% of early-onset breast cancer patients among Ashkenazi women. Am. J. Hum. Genet. 60:505 14 2. Altarescu G, Brooks B, Margalioth E, Eldar Geva T, et al. 2007. Simultaneous preimplantation genetic diagnosis for Tay-Sachs and Gaucher disease. Reprod. Biomed. Online 15:83 88 3. Altarescu G, Renbaum P, Brooks PB, Margalioth EJ, Ben Chetrit A, et al. 2008. Successful polar bodybased preimplantation genetic diagnosis for achondroplasia. Reprod. Biomed. Online 16:276 82 4. Bach G, Zeigler M, Zlotogora J. 2007. Prevention of lysosomal storage disorders in Israel. Mol. Genet. Metab. 90:353 57 5. Bar-Shira A, Rosner G, Rosner S, Goldstein M, Orr-Urtreger A. 2006. Array-based comparative genome hybridization in clinical genetics. Pediatr. Res. 60:353 58 6. Basel-Vanagaite L, Taub E, Drasinover V, Magal N, Brudner A, et al. 2008. Genetic carrier screening for spinal muscular atrophy and spinal muscular atrophy with respiratory distress 1 in an isolated population in Israel. Genet. Test. 12:53 56 7. Basel-Vanagaite L, Taub E, Halpern GJ, Drasinover V, Magal N, et al. 2007. Genetic screening for autosomal recessive nonsyndromic mental retardation in an isolated population in Israel. Eur. J. Hum. Genet. 15:250 53 8. Beutler E. 2007. Carrier screening for Gaucher disease: more harm than good? JAMA 298:1329 31 9. Beutler E, Nguyen NJ, Henneberger MW, Smolec JM, McPherson RA, et al. 1993. Gaucher disease: gene frequencies in the Ashkenazi Jewish population. Am. J. Hum. Genet. 52:85 88 10. Broide E, Zeigler M, Eckstein J, Bach G. 1993. Screening for carriers of Tay-Sachs disease in the ultraorthodox Ashkenazi Jewish community in Israel. Am. J. Med. Genet. 47:213 15 11. Carmi R, Elbedour K, Stone EM, Sheffield VC. 1995. Phenotypic differences among patients with Bardet- Biedl syndrome linked to three different chromosome loci. Am. J. Med. Genet. 59:199 203 12. Carmi R, Elbedour K, Wietzman D, Sheffield V, Shoham-Vardi I. 1998. Lowering the burden of hereditary diseases in a traditional, inbred community: ethical aspects of genetic research and its application. Sci. Context 11:391 95 13. Charrow J. 2004. Ashkenazi Jewish genetic disorders. Fam. Cancer 3:201 6 14. Dangoor N, Gazit E, Sade M, Zimin B, Frydman M. 1995. [Multidisciplinary approach to counseling in Huntington s disease]. Harefuah 128:751 54, 824 15. Ekstein J, Katzenstein H. 2001. The Dor Yeshorim story: community-based carrier screening for Tay-Sachs disease. Adv. Genet. 44:297 310 16. Feldman GE. 2001. Do Ashkenazi Jews have a higher than expected cancer burden? Implications for cancer control prioritization efforts. Isr. Med. Assoc. J. 3:341 46 www.annualreviews.org Genetic Testing in Israel 8.15

17. Foulkes WD, Thiffault I, Gruber SB, Horwitz M, Hamel N, et al. 2002. The founder mutation MSH2 1906G >C is an important cause of hereditary nonpolyposis colorectal cancer in the Ashkenazi Jewish population. Am. J. Hum. Genet. 71:1395 412 18. Gan-Or Z, Giladi N, Rozovski U, Shifrin C, Rosner S, et al. 2008. Genotype-phenotype correlations between GBA mutations and Parkinson disease risk and onset. Neurology 70:2277 83 19. Gavert N, Yaron Y, Naiman T, Bercovich D, Rozen P, et al. 2002. Molecular analysis of the APC gene in 71 Israeli families: 17 novel mutations. Hum. Mutat. 19:664 20. Gazit E, Lubomirov L, Munakov O, Topper A, Frydman M, et al. 1998. Distribution of CAG repeats in normal and Huntington s disease patients in Israel. Clin. Genet. 54:250 51 21. Gofin R, Adler B, Palti H. 2004. Screening tests in prenatal care: a national study in Israel. Isr. Med. Assoc. J. 6:535 39 22. Goldberg Y, Porat RM, Kedar I, Shochat C, Sagi M, et al. 2008. Mutation spectrum in HNPCC in the Israeli population. Fam. Cancer 7:309 17 23. Guillem JG, Rapaport BS, Kirchhoff T, Kolachana P, Nafa K, et al. 2003. A636P is associated with early-onset colon cancer in Ashkenazi Jews. J. Am. Coll. Surg. 196:222 25 24. Hedayat KM, Shooshtarizadeh P, Raza M. 2006. Therapeutic abortion in Islam: contemporary views of Muslim Shiite scholars and effect of recent Iranian legislation. J. Med. Ethics 32:652 57 25. Horowitz M, Pasmanik-Chor M, Borochowitz Z, Falik-Zaccai T, Heldmann K, et al. 1998. Prevalence of glucocerebrosidase mutations in the Israeli Ashkenazi Jewish population. Hum. Mutat. 12:240 44 26. Jaber L, Bailey-Wilson JE, Haj-Yehia M, Hernandez J, Shohat M. 1994. Consanguineous matings in an Israeli-Arab community. Arch. Pediatr. Adolesc. Med. 148:412 15 27. Jaber L, Dolfin T, Shohat T, Halpern GJ, Reish O, Fejgin M. 2000. Prenatal diagnosis for detecting congenital malformations: acceptance among Israeli Arab women. Isr. Med. Assoc. J. 2:346 50 28. Jaber L, Halpern GJ, Shohat T. 2000. Trends in the frequencies of consanguineous marriages in the Israeli Arab community. Clin. Genet. 58:106 10 29. Kaback M, Lim-Steele J, Dabholkar D, Brown D, Levy N, Zeiger K. 1993. Tay-Sachs disease carrier screening, prenatal diagnosis, and the molecular era. An international perspective, 1970 to 1993. The International TSD Data Collection Network. JAMA 270:2307 15 30. Kadouri L, Hubert A, Rotenberg Y, Hamburger T, Sagi M, et al. 2007. Cancer risks in carriers of the BRCA1/2 Ashkenazi founder mutations. J. Med. Genet. 44:467 71 31. Kannai R, Chertok IR. 2006. Prenatal panel screening considerations for non-neuronopathic Gaucher disease in the Ashkenazi-Jewish population. Isr. Med. Assoc. J. 8:347 50 32. Kedar-Barnes I, Rozen P. 2004. The Jewish people: their ethnic history, genetic disorders and specific cancer susceptibility. Fam. Cancer 3:193 99 33. Kerem E, Kalman YM, Yahav Y, Shoshani T, Abeliovich D, et al. 1995. Highly variable incidence of cystic fibrosis and different mutation distribution among different Jewish ethnic groups in Israel. Hum. Genet. 96:193 97 34. Lavie O, Gruber SB, Lejbkowicz F, Dishon S, Rennert G. 2008. Gynecologic malignancies in Ashkenazi families with the MSH2 A636P founder mutation. Am. J. Obstet. Gynecol. 199:148e1 3 35. Lerer I, Wang T, Peretz T, Sagi M, Kaduri L, et al. 1998. The 8765delAG mutation in BRCA2 is common among Jews of Yemenite extraction. Am. J. Hum. Genet. 63:272 74 36. Levy-Lahad E, Catane R, Eisenberg S, Kaufman B, Hornreich G, et al. 1997. Founder BRCA1 and BRCA2 mutations in Ashkenazi Jews in Israel: frequency and differential penetrance in ovarian cancer and in breast-ovarian cancer families. Am. J. Hum. Genet. 60:1059 67 37. Lynch HT, de la Chapelle A. 2003. Hereditary colorectal cancer. N. Engl. J. Med. 348:919 32 38. Lynch HT, Rubinstein WS, Locker GY. 2004. Cancer in Jews: introduction and overview. Fam. Cancer 3:177 92 39. Malcov M, Ben-Yosef D, Schwartz T, Mey-Raz N, Azem F, et al. 2005. Preimplantation genetic diagnosis (PGD) for Duchenne muscular dystrophy (DMD) by triplex-nested PCR. Prenat. Diagn. 25:1200 5 40. Malcov M, Naiman T, Yosef DB, Carmon A, Mey-Raz N, et al. 2007. Preimplantation genetic diagnosis for fragile X syndrome using multiplex nested PCR. Reprod. Biomed. Online 14:515 21 41. Malcov M, Schwartz T, Mei-Raz N, Yosef DB, Amit A, et al. 2004. Multiplex nested PCR for preimplantation genetic diagnosis of spinal muscular atrophy. Fetal. Diagn. Ther. 19:199 206 8.16 Rosner Rosner Orr-Urtreger

42. Mishori Dery A, Carmi R, Shoham Vardi I. 2007. Different perceptions and attitudes regarding prenatal testing among service providers and consumers in Israel. Community Genet. 10:242 51 43. Navon R, Proia RL. 1991. Tay-Sachs disease in Moroccan Jews: deletion of a phenylalanine in the alphasubunit of beta-hexosaminidase. Am. J. Hum. Genet. 48:412 19 44. Nevo Y, Ahituv S, Yaron Y, Kedmi M, Shomrat R, et al. 2001. Novel mutations in the emerin gene in Israeli families. Hum. Mutat. 17:522 45. Orr-Urtreger A, Shifrin C, Rozovski U, Rosner S, Bercovich D, et al. 2007. The LRRK2 G2019S mutation in Ashkenazi Jews with Parkinson disease: Is there a gender effect? Neurology 69:1595 602 46. Ostrer H. 2001. A genetic profile of contemporary Jewish populations. Nat. Rev. Genet. 2:891 98 47. Peleg L, Karpati M, Gazit E, Raas-Rothschild A, Goldman B. 1994. Mutations of the hexosaminidase A gene in Ashkenazi and non-ashkenazi Jews. Biochem. Med. Metab. Biol. 52:22 26 48. Quint A, Lerer I, Sagi M, Abeliovich D. 2005. Mutation spectrum in Jewish cystic fibrosis patients in Israel: implication to carrier screening. Am. J. Med. Genet. A 136:246 48 49. Quintana-Murci L, Gal I, Bakhan T, Quach H, Sayar SH, et al. 2005. The Tyr978X BRCA1 mutation: occurrence in non-jewish Iranians and haplotype in French-Canadian and non-ashkenazi Jews. Fam. Cancer 4:85 88 50. Raz AE, Atar M, Rodnay M, Shoham-Vardi I, Carmi R. 2003. Between acculturation and ambivalence: knowledge of genetics and attitudes towards genetic testing in a consanguineous Bedouin community. Community Genet. 6:88 95 51. Remennick L. 2006. The quest for the perfect baby: Why do Israeli women seek prenatal genetic testing? Sociol. Health. Illn. 28:21 53 52. Roa BB, Boyd AA, Volcik K, Richards CS. 1996. Ashkenazi Jewish population frequencies for common mutations in BRCA1 and BRCA2. Nat. Genet. 14:185 87 53. Rozen P, Naiman T, Strul H, Taussky P, Karminsky N, et al. 2002. Clinical and screening implications of the I1307K adenomatous polyposis coli gene variant in Israeli Ashkenazi Jews with familial colorectal neoplasia. Evidence for a founder effect. Cancer 94:2561 68 54. Rozen P, Shomrat R, Strul H, Naiman T, Karminsky N, et al. 1999. Prevalence of the I1307K APC gene variant in Israeli Jews of differing ethnic origin and risk for colorectal cancer. Gastroenterology 116:54 57 55. Sheffield VC, Stone EM, Carmi R. 1998. Use of isolated inbred human populations for identification of disease genes. Trends. Genet. 14:391 96 56. Sheiner E, Shoham-Vardi I, Weitzman D, Gohar J, Carmi R. 1998. Decisions regarding pregnancy termination among Bedouin couples referred to third level ultrasound clinic. Eur. J. Obstet. Gynecol. Reprod. Biol. 76:141 46 57. Sher C, Romano-Zelekha O, Green MS, Shohat T. 2003. Factors affecting performance of prenatal genetic testing by Israeli Jewish women. Am. J. Med. Genet. A 120A:418 22 58. Sher C, Romano-Zelekha O, Green MS, Shohat T. 2004. Utilization of prenatal genetic testing by Israeli Moslem women: a national survey. Clin. Genet. 65:278 83 59. Shohat M, Frimer H, Shohat-Levy V, Esmailzadeh H, Appelman Z, et al. 2003. Prenatal diagnosis of Down syndrome: ten year experience in the Israeli population. Am. J. Med. Genet. A 122A:215 22 60. Simchoni S, Friedman E, Kaufman B, Gershoni-Baruch R, Orr-Urtreger A, et al. 2006. Familial clustering of site-specific cancer risks associated with BRCA1 and BRCA2 mutations in the Ashkenazi Jewish population. Proc. Natl. Acad. Sci. USA 103:3770 74 61. Struewing JP, Abeliovich D, Peretz T, Avishai N, Kaback MM, et al. 1995. The carrier frequency of the BRCA1 185delAG mutation is approximately 1 percent in Ashkenazi Jewish individuals. Nat. Genet. 11:198 200 62. Toledano-Alhadef H, Basel-Vanagaite L, Magal N, Davidov B, Ehrlich S, et al. 2001. Fragile-X carrier screening and the prevalence of premutation and full-mutation carriers in Israel. Am. J. Hum. Genet. 69:351 60 63. Yaron Y, Heifetz S, Ochshorn Y, Lehavi O, Orr-Urtreger A. 2002. Decreased first trimester PAPP-A is a predictor of adverse pregnancy outcome. Prenat. Diagn. 22:778 82 64. Yaron Y, Ochshorn Y, Heifetz S, Lehavi O, Sapir Y, Orr-Urtreger A. 2002. First trimester maternal serum free human chorionic gonadotropin as a predictor of adverse pregnancy outcome. Fetal Diagn. Ther. 17:352 56 www.annualreviews.org Genetic Testing in Israel 8.17

65. Yaron Y, Schwartz T, Mey-Raz N, Amit A, Lessing JB, Malcov M. 2005. Preimplantation genetic diagnosis of Canavan disease. Fetal Diagn. Ther. 20:465 68 66. Zimran A, Zaizov R, Zlotogora J. 1997. [Large scale screening for Gaucher s disease in Israel a position paper by the National Gaucher Committee of the Ministry of Health]. Harefuah 133:107 8 67. Zlotogora J. 1997. Autosomal recessive diseases among Palestinian Arabs. J. Med. Genet. 34:765 66 68. Zlotogora J. 2002. Molecular basis of autosomal recessive diseases among the Palestinian Arabs. Am. J. Med. Genet. 109:176 82 69. Zlotogora J. 2002. Parental decisions to abort or continue a pregnancy with an abnormal finding after an invasive prenatal test. Prenat. Diagn. 22:1102 6 70. Zlotogora J, Bach G, Munnich A. 2000. Molecular basis of Mendelian disorders among Jews. Mol. Genet. Metab. 69:169 80 71. Zlotogora J, Barges S, Bisharat B, Shalev SA. 2006. Genetic disorders among Palestinian Arabs. 4: genetic clinics in the community. Am. J. Med. Genet. A 140:1644 46 72. Zlotogora J, Haklai Z, Leventhal A. 2007. Utilization of prenatal diagnosis and termination of pregnancies for the prevention of Down syndrome in Israel. Isr. Med. Assoc. J. 9:600 2 73. Zlotogora J, Reshef N. 1998. Prenatal testing for genetic disorders among Arabs. Prenat. Diagn. 18:219 24 74. Zuckerman S, Lahad A, Shmueli A, Zimran A, Peleg L, et al. 2007. Carrier screening for Gaucher disease: lessons for low-penetrance, treatable diseases. JAMA 298:1281 90 8.18 Rosner Rosner Orr-Urtreger