Medical genetics around the world - BMJ

Medical genetics around the world

Journal of Medical Genetics 1989, 26, 179-189

Medical genetics in IsraelR M GOODMAN*t, B BONNE-TAMIRt, A ADAMt, R VOSS§**, G BACH§,Y SHILOHt, M BAT-MIRIAM KATZNELSON*t, G BARKAI*t, B GOLDMAN*t,B PADEH*t, J CHEMKE§1I, AND C LEGUMt¶From *the Institute of Medical Genetics, The Chaim Sheba Hospital; tDepartment of Human Genetics,Sackler School of Medicine, Tel-Aviv University; JtDepartment of Biology, Everyman's University;WDepartment of Human Genetics, Hadassah University Hospital, Hebrew University; IKaplan Hospital,Rehovot; and ¶Ichilov Hospital, Tel-Aviv, Israel.

When I was asked to write this article on humangenetics in Israel, I was pleased to accept thechallenge, but after pondering the subject for aperiod of time, I began to see some of the difficultiesin such an undertaking, owing to the great amoufntof investigative studies that has taken place in ourcountry. My major concern was the unintentionalomission of important historical information alongwith scientific contributions to this broad andrapidly advancing field. I decided that the best wayto handle this problem would be to call upon certainof my colleagues and ask them to write on thedevelopment and progress in their special areas.Despite all of our combined efforts I am certain thatomissions must have occurred, but we hope thatunderstanding will prevail and that time and spacewill also be taken into consideration.As this paper was nearing completion one of our

key contributors, Dr Ruth Voss of the HadassahUniversity Hospital of the Hebrew University,suddenly died in a tragic car accident. Because shewas such an outstanding person as well as a humancytogeneticist, we would like to dedicate this articleto her blessed memory.

Historical background

Matters of genetic concern have been an integralpart of Jewish life dating from the Biblical period. Inthe Torah (first five books of Moses) book ofGenesis (chapter 30, lines 32-43) one can find awritten account of Jacob's breeding experimentswith his father in law's sheep and goats. In the bookof Leviticus (chapter 18, lines 6-18) one will find

RDeceased.Received for publication 23 September 1988.Accepted for publication 30 September 1988.

specific laws stating whom one can and cannotmarry. The Babylonian Talmud compiled approxi-mately 1500 years ago is an extremely rich source forthe description of a number of human genetic mal-formations and syndromes.' For example, variouscranial, facial, and body malformations are men-tioned in Kodashim, tractate Bekhorot 44a, familialepilepsy is described in Nashim, tractate Yevamot64b, and in the same tractate and page one can finda report of haemophilia. The testicular feminisationsyndrome can be recognised from the writing anddiscussion found in Nashim, tractate Ketuboth 10b,and a clinical description of Marfan's syndrome ismentioned in Kodashim, tractate Bekhorot 45b.Analysis of the Talmud for genetic malformationsand syndromes is in its infancy and in the years tocome such studies should prove most rewarding.With a long Jewish tradition of critical thinking

about all matters pertaining to life, coupled with thenewly emerging interest in human genetics, it wasnot surprising that the modern State of Israel,established in 1948, would find itself activelyengaged in a variety of human genetic studies. Themain impetus for this initial flourish of activity camefrom the massive number of Jewish immigrantsarriving in Israel from all parts of the world. Israelimmediately became the ideal setting for studyinggenetic similarities and differences among theJewish people. In addition to investigating geneticpolymorphisms among the various Jewish communi-ties, Israeli physicians and geneticists also foundthemselves absorbed in learning about such in-herited diseases as familial Mediterranean fever,Dubin-Johnson syndrome, G6PD deficiency, thalas-saemia, and phenylketonuria to mention just a few.Although several medical centres and institutions

soon became interested in the practical and inves-tigative aspects of genetic diseases and polymorph-

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isms among the Jewish people, two centres inparticular achieved international recognition fortheir pioneering work in these areas. The HadassahUniversity Hospital and the Hebrew University inJerusalem under the guidance of the late ProfessorElizabeth Goldschmidt, and the former Tel-Hashomer Hospital (now the Chaim Sheba MedicalCentre) and the Tel-Aviv University under theinspiration and thinking of the late Professor ChaimSheba became the leading medical genetic centres inIsrael.

Israel and its people

Israel is a very small country, approximately 280miles (450 km) in length and 110 miles (180 km) atmaximum width. The majority of its total popula-tion of approximately 5 million people is clustered inthe centre of the country. Seventy-five percent of itsland is desert. The population can be divided intoJewish (4.3 million) and non-Jewish (700 000),mainly Arab-Moslems. The Jewish population cansimilarly be grouped into three major ethnicgroups.2 The oldest are the Oriental Jews (originat-ing from the continent of Asia), followed by theSephardi Jews (originating from countries of theMediterranean basin), which together comprise53% of the Jewish Israeli population. The youngestof the groups, the Ashkenazi Jews (originating fromcentral and eastern Europe), make up the remaining47% of the Jewish population. This almost equaldistribution between non-Ashkenazi (Oriental plusSephardi Jews) and Ashkenazi Jews makes theIsraeli scene an ideal place to study all geneticaspects of the Jewish people.

Human population genetics

The initial stimulus for genetic studies among thevarious Jewish ethnic groups in Israel was theimmigration in the early 1950s of over a millionJewish immigrants making 'aliyah' (literally: comingto Israel from over 100 countries in all continents).It was soon recognised that frequencies of geneticdiseases differed markedly among the various com-munities, an observation which further served as acatalyst for studying the 'genetic profiles' of thesepopulations.3 4 It therefore seems fitting that thisreport begins with Israeli studies in populationgenetics. The questions asked initially were essen-tially those that are being asked today by Israelipopulation geneticists regarding the Jewish people.

(1) How heterogeneous are each of the communi-ties?

(2) How much do they differ genetically fromeach other and from their previous host population?

(3) To what extent do the genetic data correlatewith known or surmised histories of the variousgroups?

(4) What can studies of genealogies, matingpreferences, and inbreeding patterns tell us aboutthe extent of genetic isolation of Jewish communi-ties and the directions of gene flow?Over the years, the tools and methods of human

population studies have changed considerably. Inthe beginning, Israeli geneticists, like their col-leagues elsewhere, characterised and comparedJewish ethnic groups by using frequencies of geneticmarkers such as blood groups, serum proteins,isozymes, colour vision deficiencies, taste sensitivityto PTC, finger and palm print analyses, as well asmorphological and anthropometric measurements.4While the early studies in the 1950s and 1960semphasised the differences rather than the similar-ities between the Jewish communities, some of themore recent studies point to a basic genetic similar-ity, particularly regarding blood group polymorph-isms, and to the small contribution of non-Jews tothe Jewish gene pool. In the 1970s, studies using thehistocompatibility antigens (HLA system) providednew data allowing renewed examination of thehistorical-geographical groupings of Jewish exiles.-8Findings indicated elements of a common origin formost of the major Jewish ethnic groups, as well as anabsence of substantial gene influx from non-Jewishpopulations into the Jewish gene pool. Previousthinking that Jews of any given area tend toresemble the non-Jews of that area more closelythan they do one another was not substantiated bythe abundant polymorphic data accumulated, nor bythe recognition of an increasing number of specificJewish genetic diseases.

Furthermore, multivariate statistical methodssuch as estimates of genetic distances or clusteranalysis, based on a large number of genetic loci,supported the contention that not much admixturehad taken place between European Jews (Ash-kenazi) and their gentile neighbours.6 7 9Also some Oriental Jews, like those from Iraq,

have genetically far more in common with Ash-kenazi Jews (central and east European Jews) thaneither group has with the non-Jews among whomthey have lived for centuries.As one might expect, there are also exceptions to

this-overall picture of relative Jewish distinctiveness.Jews from Yemen are a case in point; they have agenetic make up that is characteristic of the Arabianpeninsula which probably indicates a massive gene-tic contribution into the small pre-existing Jewishcommunity from indigenous tribes who converted toJudaism in the fourth or fifth centuries. A similarsituation exists with regard to Cochin Jews10 11 and

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Medical genetics in Israel

local Kerala Indians and with regard to the Ethio-pian Jews'2 and the non-Jewish Ethiopian tribes.Thus these Jewish communities are geneticallylinked to their non-Jewish 'hosts' and have little incommon with other Oriental, Sephardi, or Ashke-nazi Jewish groups.

Present efforts of population genetic studies inIsrael aim to scrutinise genetic variation at themolecular level and to re-examine genetic diversityamong the ethnic communities using DNA poly-morphisms. Results of restriction endonucleasefragment patterns in mitochondrial DNA whichhave been investigated in several Israeli groups tendto support conclusions drawn earlier regarding thesimilarity between European and North AfricanJews.13 On the other hand, mtDNA in Yemeniteand Ethiopian Jews demonstrates unique and groupspecific patterns which reflect their isolation.Before concluding this section, it is worthwhile to

point out that Israeli population geneticists havealso directed considerable effort to studying variousnon-Jewish ethnic groups in the country,such as Arabs, Armenians, Druze, and Circassians.Perhaps the two most extensive studies of non-Jewsthat have been done are on the Samaritans, a uniquereligious sect and isolate of about 500 members,tracing their origins back to the ancient Israelites,14and on the Bedouin tribes of South Sinai.

Clinical genetics

In the 1950s few physicians thought much about therole of genetic factors influencing disease. However,in Israel during these years, with the influx ofthousands of Jews into the country from all parts ofthe world, Israeli physicians found themselves con-fronted with patients with symptoms and findingsunfamiliar to them. The fact that they observedsimilar and often identical features in other familymembers stimulated them to think in terms of apossible genetic aetiology for the disorders inquestion. The frequent presence of close parentalconsanguinity coupled with affected sibs became thegenetic hallmark for a number of newly recognisedautosomal recessive diseases in the Sephardi andOriental Jewish communities in Israel.'5 Geneticdisorders among the Ashkenazi community for themost part had been either previously describedelsewhere, or were later to be recognised within theAshkenazi communities of Israel and the UnitedStates.'6 Thus, Israel's major contribution to theclinical recognition and description of genetic dis-orders among the Jewish people involves mainlythose conditions which affect the non-Ashkenazicommunities (Oriental and Sephardi Jews). This isunderstandable as the Ashkenazi community (83%

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of world Jewry) is concentrated mainly in thewestern world where the level of investigativemedicine is the highest. Within a relatively shortperiod of time (approximately 10 years) the Jewishcommunities in Israel could be characterised bythose genetic diseases having a high frequency in thevarious ethnic groups.The approach to investigating these disorders was

basically a multidisciplinary one and involved notonly the team efforts of Israeli geneticists, biochem-ists, and clinicians, but also international talent aswell. Those who were part of these teams cherishthe memories that these investigative studies evokedin terms of splendid cooperation and scientificexcitement.By the year 1962 such an enormous wealth of

genetic information on diseases and polymorphismsin Israeli Jews had been amassed that the lateProfessor Goldschmidt organised an internationalconference held in Jerusalem and entitled Thegenetics of migrant and isolate populations. 3 Elevenyears later an update conference entitled Geneticpolymorphisms and diseases in man4 was organisedin Tel-Aviv to honour the passing of the lateProfessor Chaim Sheba.As one would expect, time and scientific advances

have changed the direction of clinical genetics inIsrael. New genetic diseases and rare syndromes arestill being recognised, mainly in the non-Ashkenazicommunities, but at a much slower pace. However,there is still much to learn about genetic disordersamong Israel's non-Jewish groups and this is beingevaluated slowly.Today in Israel, clinical geneticists are teaming up

with molecular geneticists for purposes of linkagestudies, prenatal diagnosis, gene mapping, genecloning, and eventually treatment of genetic dis-eases. In addition, we are interested in investigatinga number of genetic syndromes for their phenotypicheterogeneity, and then having our colleagues inmolecular genetics evaluate the degree of hetero-geneity existing at the molecular level. As in othercountries, clinical geneticists play a key role in thediagnosis of genetic disorders, providing geneticcounselling and actively participating in prenataldiagnosis. Almost all major medical centres in Israelhave one or more clinical geneticists, and although awell defined training programme in clinical geneticshas not yet been established in Israel, this willundoubtedly be organised in the very near future. Aone year fellowship programme in Jewish geneticdiseases has been established at the Sheba MedicalCentre and its first fellow began her studies in theautumn of 1988. Several Israeli physicians, aftercompleting their speciality training, have been sentabroad for training in clinical genetics. Despite all of



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our efforts . to maintain an adequate number ofpeople in clinical genetics, there is still a dire needfor more.

Cytogenetics

The basis for the development of human cytogene-tics in Israel was the group created at the HebrewUniversity in Jerusalem by Professor Jacob Wahr-man. His experience in mammalian cytogenetics17has been extremely important in the studies of onemore mammal, namely Homo sapiens, at thecytogenetic level. In February 1958, the first humanmaterial was obtained. This was testicular tissuewhich yielded meiotic cells of good quality. Thedevelopment of methods for processing peripheralblood for chromosome studies of mitotic cellsenabled the start of cytogenetic studies for medicalpurposes and contributed to the role of chromosomeaberrations in the aetiology of congenital malforma-tion syndromes.'20With the increasing demand for cytogenetic

studies it became necessary to provide for thetraining of professional staff with a background ingenetics, cytology, and cell biology. A number ofgraduates, from the Department of Genetics inJerusalem, has contributed to the further growthand spread of human cytogenetics all over thecountry.

Since the early 1960s other medical centres havebegun human cytogenetic studies and today 10laboratories are actively engaged in studies usingperipheral blood for clinical cases and bone marrowand solid tumours in malignancies. Prenatalcytogenetics using amniotic cells is performed in fivecentres, while chorionic villus placental and cordblood sampling are performed in selected centres.Areas of special scientific interest in human

cytogenetics include the chromosome breakage syn-21 22drome ataxia telangiectasia. The finding of a

clastogenic23 factor in the amniotic fluid of anaffected patient opened up new possibilities forprenatal diagnosis.24 One of the first prenataldiagnoses of Fanconi's anaemia was performed inJerusalem.25 The complex syndrome of X linkedmental retardation with the fragile site at Xq27 isbeing studied extensively at the chromatin level.Studies on human meiosis are continuing in Profes-sor Wahrman's laboratory especially in relation tosubfertility.26 Studies on the sensitivity of spindlefibres to various agents and its relation to meioticnon-disjunction are performed in Professor Avivi'slaboratory in Tel-Aviv University. Dr F Shabtai inHasharon Hospital is specifically interested in therole of fragile sites and heterochromatic regions inthe aetiology of malignancies.

A new class of chromosome bands, 'D bands', hasbeen defined on the basis of the sensitivity of humanchromosomes to DNAse I. This work27 has beendone in the laboratory of the late Menashe Marcus.

Analysis of chromosomal aberrations is nowentering a new era; molecular analysis using specificprobes for chromosome markers (for example,alphoid probes for specific centromeres, Y chromo-some specific sequences) will be applied in theDepartment of Human Genetics, Hadassah MedicalCentre in Jerusalem as well as in the Sackler Schoolof Medicine in Tel-Aviv. It is hoped that with thesenew methods, coupled with the wealth of clinicalmaterial, we shall continue to contribute to theadvancement of human cytogenetics.

Biochemical genetics

The study of lysosomal storage disorders in variousethnic groups in Israel shows the unique structure ofIsraeli society and illustrates some unusual findingsin certain Israeli communities which will be outlinedhere.The two most frequent storage disorders in Israel

are Gaucher's disease and Tay-Sachs disease andthis is attributed to the fact that Ashkenazi Jewscomprise approximately 50% of the Israeli Jewishpopulation. However, detailed evaluation of Tay-Sachs patients in Israel showed a high proportion ofpatients of Jewish Moroccan origin. This fact wasfurther established by a preliminary screening pro-gramme among the Moroccan Jewish community inIsrael,28 the results of which indicated a heterozy-gote frequency of 1/60, similar to the 1/30 Tay-Sachscarrier frequency among the Ashkenazim, andcontrasting with the 1/300 carrier frequency amongnon-Jews or Jews of other origins.' This findingjustifies the current policy of including the Jews ofMoroccan origin in the countrywide screening pro-gramme performed in Israel since 1975 for thedetection of Tay-Sachs carriers. It is not clear yetwhether the Ashkenazi and Moroccan Jews have thesame or different mutations in the a chain gene ofhexosaminidase. This awaits detailed analysis of thegene itself in both groups of patients.

In addition to the classic infantile type of Tay-Sachs disease among Ashkenazi Jews, 15 subjectsfrom this ethnic group with the adult form werereported.29 The clinical picture varied among thesepatients, but in all except one central nervoussystem malfunction was observed. The precisefrequency of this phenotype among Ashkenazi Jewsis not clear, but it must undoubtedly be rare.Biochemical analysis of cultured fibroblasts fromadult type patients indicated the existence of acompound heterozygote in the a chain locus,

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consisting of the classic Tay-Sachs mutation with noa chain biosynthesis and a second mutation affectingthe association of the remaining a chains with the ,3chains of hexosaminidase.

Israel is characterised by the existence of geneticisolates in Jewish and Arabic communities. Thesecommunities are also characterised by a high degreeof consanguinity. As expected in these cases arelatively high frequency of genetic disorders iscommon in each community, but unexpected lyso-somal storage disorders comprise a large proportionof the recessive disorders, while these disorders arerelatively rare in the general population. The factthat these disorders can be tested biochemically andheterozygotes can usually be unambiguously identi-fied enabled us to conduct screening programmes toassess the frequency of the mutant gene in some ofthese communities and to identify heterozygouscouples and offer them prenatal diagnosis. Theseprogrammes have caused a dramatic decrease in thebirth of affected children. Two examples are illus-trated below.

(1) The Habbanite Jews originate from the city ofHaban in the south-east of Saudi Arabia. Theyimmigrated to Israel at the beginning of the 1950sand still constitute a closed community with a highdegree of consanguinity. Late infantile metachroma-tic leucodystrophy (MLD) occurs in this communitywith a high frequency.30 MLD is a neurodegenera-tive lysosomal storage disorder, caused by defi-ciency of sulphatide sulphatase. The life expectancyof the late infantile variant is six to eight years.Biochemical diagnosis and detailed examination ofmedical records of Habbanite children who diedduring the last 25 years indicated the occurrence ofone MLD patient in every 75 live births compared to1/40 000 in the general population. Screening pro-grammes for the detection of MLD heterozygotes inthis community indicated a carrier frequency of18%, which is in good agreement with the patientdata. Couples where both spouses are MLD hetero-zygotes have been identified and prenatal testing isoffered to these couples.

(2) A similar phenomenon was seen in a Druzecommunity in the north of Israel. This community isalso characterised by a high degree of consanguinity.Seven patients with Krabbe's disease were recentlydiagnosed in this population.31 Krabbe's disease is asevere neurodegenerative lysosomal storage dis-order caused by deficiency of galactocerebrosidase.Life expectancy is one to two years. Genetic analysisof these families indicated a heterozygote frequencyfor the Krabbe gene of 1/150 among the Druzecompared to 1/100 000 in the general population.These two examples illustrate the potential which

appropriate medical services can achieve, namely

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the prevention of the birth of children affected withsevere, incurable disorders by operating properscreening programmes and parallel education of therelevant population. This depends, of course, on theavailability of reliable laboratory assay techniquesfor the detection of heterozygotes and affectedfetuses.

Hunter's syndrome (mucopolysaccharidosis IIDoccurs with a relatively high frequency in the Jewishpopulation in Israel compared to other westernpopulations, particularly among the AshkenaziJews.32 33 Genetic analysis of Ashkenazi families inIsrael with Hunter's syndrome patients indicated theabsence of new mutations, which is expected in Xlinked disorders such as Hunter's syndrome. Whileapproximately one-third of Hunter's syndromepatients in non-Jewish populations is thought toresult from new mutations, all the Hunter's patients'mothers in the Ashkenazi families were identified asHunter heterozygotes and so were the maternalgrandmothers when this could be tested. Further-more, in all the Ashkenazi families with Hunter'ssyndrome patients, a clear selection in favour of theHunter gene was evident,34 so that an unusuallyhigh proportion of family members of these patientswere either heterozygous females or affected males.The cause of this phenomenon has not beenelucidated yet and could stem from heterozygoteadvantage, or from pre- or postzygotic selection.Whatever the cause, this phenomenon explains thehigh frequency of Hunter's syndrome in the Jewishpopulation.Most of the carriers of Hunter's syndrome in

Israel were detected by appropriate enzyme assays.35A new concept developed recently allows earlyprenatal diagnosis of Hunter's syndrome, inaddition to the common procedures such as amnio-centesis and chorionic villus sampling. A consistentincrease of iduronate sulphate sulphatase, thedeficient hydrolase in Hunter's syndrome, in theserum of pregnant women was found only when thefetus was not affected with Hunter's syndrome.36This increase in enzyme activity was noted as earlyas the eighth to tenth week of pregnancy. On theother hand, when the fetus was affected withHunter's syndrome, enzyme levels in the serum ofthe heterozygous mother remained unchanged untilthe termination of the pregnancy (at least 16 to 20weeks of pregnancy). In other words, a clearcorrelation between the increase of enzyme activityin maternal serum and the status of the fetus withregard to Hunter's syndrome could be established.37The source of the enzyme increase during pregnancyis under investigation and could stem either from thefetus itself or from the membranes surrounding it.

Mucolipidosis type IV (MLIV), a recently recog-



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nised lysosomal storage disorder, is found in Ashke-nazi Jews with a high frequency.38 Though theprecise frequency has not been assessed as yet, mostof the 40 patients known today are of AshkenaziJewish origin. The disorder is clinically charac-terised by psychomotor retardation, comealopacities, and retinal degeneration. It was recentlyshown that MLIV is involved in the storage ofgangliosides, mucopolysaccharides, and phospho-lipids.39 40 Ganglioside sialidase is deficient in thesepatients.41 Prenatal diagnosis is performed byelectron microscopic observation of the typicalinclusion bodies in cultured amniotic fluid cells inMLIV fetuses.42The work described here illustrates the import-

ance of biochemical evaluation of genetic disordersas a powerful tool in preventive medicine. We shalltherefore focus our future endeavours in theseareas. This should be achieved by identifying thebiochemical defect in those genetic disorders wherethe defect is not characterised as yet, mainly thosedisorders found in relatively high frequency inspecific communities in Israel, such as familialdysautonomia in the Ashkenazi Jews, or albinismand mental retardation in certain Arabic communi-ties. This should lead to the development of reliableassay techniques for unambiguous diagnosis ofpatients, heterozygotes, and affected fetuses beforeinitiating mass screening in the relevant population.

Molecular genetics

The use of molecular probes for diagnostic purposesbegan in Israel in 1981, when a group of molecularbiologists at the Medical School of the HebrewUniversity of Jerusalem and the Department ofHaematology at the Hadassah Medical Centrejoined forces to introduce the first prenatal diagnosisof thalassaemia and sickle cell anaemia in Israelusing globin probes. Since 1985, five additionallaboratories in Jerusalem, the Tel-Aviv area, andBeersheva have initiated the use of molecularprobes for prenatal diagnosis of cystic fibrosis,Duchenne muscular dystrophy, haemophilia,phenylketonuria, and 21-hydroxylase deficiency,and are preparing for routine diagnosis of the fragileX syndrome, adult polycystic kidney disease,Huntington's disease, and neurofibromatosis.

Molecular cytogenetics, that is, the analysis ofchromosomal aberrations with molecular probes, isin its infancy at the Medical School of Tel-AvivUniversity. An extensive repository of X chromo-some and autosomal probes has been established forthis purpose.

Since the medical genetics community in Israel issmall, the periodic meetings of the Israeli Society of

Medical Genetics enable all the members of thiscommunity to learn about the progress being madein each laboratory.

Basic research with direct implications for medicalgenetics is carried out in Israel's universities and atthe Weizmann Institute of Science. The Jerusalemgroup associated with the Departments of Haema-tology and Cellular Biochemistry at the Hadassah-Hebrew University Medical School has initiated twoprojects related to haemoglobin disorders: molecu-lar analysis of j3 thalassaemia mutations in the Israelipopulation is being performed using conventionaland oligonucleotide probes,43 and new vectors forgene therapy of thalassaemia and sickle cell anaemiaare being developed.44 At the Weizmann Instituteof Science, a long term project aimed at the analysisof the portion of chromosome 21 responsible forDown's syndrome was initiated by molecular clon-ing of the genes for human Cu/Zn superoxidedismutase4547 and liver type phosphofructokinase.Laboratory models for overproduction of super-oxide dismutase have been constructed in culturedcells47 48 and in transgenic mice.49 Another group atthe Weizmann Institute has recently cloned the genefor human glucocerebrosidase50 and the probes arebeing used for the molecular analysis of Gaucher'sdisease in Israel.

Several groups at Tel-Aviv University areapplying 'reverse genetics' to the identification andisolation of human disease genes. A first steptowards the molecular cloning of the gene forxeroderma pigmentosum (XP) has recently beenmade at the Faculty of Life Sciences of thisUniversity, where a successful 'correction' of theUV sensitive phenotype of XP cells was achieved bygene transfer.51 At the Medical School in Tel-Aviv,the first chromosomal assignment of the locus forWilson's disease (to chromosome 13) has been madeby linkage analysis with classical52 53 and molecular54markers. The disease gene is being approached bylinkage analysis performed with RFLPs usingseveral Israeli families, in collaboration with anAmerican group.Also in Tel-Aviv University Medical School,

regional localisation of the locus for X linkedalbinism-deafness syndrome (ALDS) to Xq25-26was achieved by linkage analysis with RFLPs.55Detailed analysis of the mutations causing phenylke-tonuria in Israel is under way and has alreadyrevealed a single gene deletion which accounts forall the PKU cases among the Yemenite Jews.56 Agroup at the Hebrew University of Jerusalem hasrecently identified the first close association be-tween specific RFLPs at the HLA locus and pem-phigus vulgaris.57The large number of rare genetic diseases seen in

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Israel among the various Jewish and non-Jewishcommunities offers a rich source of investigation formolecular geneticists in this country.

Dermatoglyphics

The study of dermatoglyphics in Israel began in thelate 1950s with a project analysing the digitalpatterns of 5000 Jewish males from eight differentethnic groups.58 This study showed that Jews differdermatoglyphically from their former host non-Jewish neighbours, but there is a similarity betweenJewish finger prints and those of non-Jewish popula-tions from the Middle East. Thus, it was concludedthat there exists an Eastern Mediterranean genepool which involves all of the inhabitants of thisarea.

This study was the precursor of others on variousJewish groups and a number of isolates such as theSamaritans, Habbanites, the Falasha, and IndianJews.59-61Because genetic distance between Jewish Israeli

populations of different geographical extraction issimilar, investigative studies have confirmed thatselected dermatoglyphic traits are suitable for calcu-lating interpopulation distance coefficients.9 62Moreover it has been shown that the similaritybetween different Jewish groups conformed to thefindings in diverse Caucasian samples, confirmingthe discriminating possibilities of palmar dermato-glyphics related to the main human races.

In the 1960s it became clear that patients withcertain autosomal and sex chromosomal syndromes(for example, Down's syndrome, XO, XXY, etc)had distinct and characteristic dermatoglyphic pat-terns. These changes were also noted in fetusesterminated between the 20th and 24th week ofgestation.63 In addition our studies in Israel showedthat these typical dermatoglyphic patterns weresuperimposed on the existing dermatoglyphic differ-ences between Jews and non-Jews.' 5 We investi-gated dermatoglyphic patterns in specific Jewishgenetic diseases, like Tay-Sachs disease and familialdysautonomia, plus other inborn errors of metabol-ism, but did not find any distinct features. On theother hand, we have shown that in some geneticsyndromes involving the hands (such as Tel-Hashomer camptodactyly66) and wrinkly skinsyndrome67 distinct and even diagnostic changes arepresent.An extensive study on the biological significance

of two kinds of dermatoglyphic asymmetry, direc-tional and fluctuating, is being performed at Tel-Aviv University. Directional asymmetry can beregarded as a developmentally controlled traitpresumably having a genetic basis, while fluctuating

asymmetry is thought to result from the inability ofthe fetus to buffer various stress factors duringembryogenesis. There is preliminary evidence tosuggest that males are biologically less buffered thanfemales against environmental stress during theprenatal period.68

Prenatal diagnosis

AMNIOCENTESISAmniocentesis is performed in almost every medicalcentre in Israel. Those peripheral hospitals which donot have cytogenetic laboratories transfer amnioticfluid samples to one of the major regional medicalcentres. The procedure itself is done by either director indirect ultrasonic guidance.

Amniocentesis is free of charge above the age of37 years (hopefully this will be changed to 35 yearsin the near future) and also for other indications,such as a previous pregnancy with a severe geneticdisease diagnosable by means of amniocentesis.Every amniotic fluid sample is examined for AFPlevels in order to detect open neural tube defects,even if the indication for the amniocentesis hadnothing to do with a possible neural defect.69Other indications for amniocentesis are fetal sex

determination and inherited metabolic diseases,such as Tay-Sachs disease and cystic fibrosis. Owingto the small distances between the regional centresand the good communication between the medicalcentres in the country it is not necessary for allbiochemical tests to be carried out in each of themedical centres. One can choose between the optionof sending the candidate to other centres for bothamniocentesis and biochemical analysis of thesample and that of sending the sample only.

CHORIONIC VILLUS SAMPLING (CVS)In a few of our medical centres, CVS is competingstrongly as an alternative to amniocentesis. Theindications for the procedure are those for amnio-centesis, but also DNA analysis for single genediseases, such as Duchenne muscular dystrophy,PKU, cystic fibrosis, and haemophilia. It is alsopossible to use CVS for the enzymatic diagnosis ofTay-Sachs disease and many other inborn errors ofmetabolism. In Israel, the Sheba Medical Centre hasthe most experience with CVS having done morethan 250 diagnostic procedures with a 2-5% risk ofcomplications.

SERUM a FETOPROTEIN (AFP)Serum AFP is examined in almost every pregnancybetween the 16th and 19th week of gestation. AnAFP concentration of 2-5 x MOM (multiple ofmedian) is considered as an indication for genetic

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counselling and thorough ultrasonographic evalua-tion with the possibility of amniocentesis. We haveshown70 that AFP can be measured as early as thefirst trimester in maternal serum. There are signifi-cant differences in mean AFP values between 10 and12 weeks' gestation. Four samples analysed forchromosomal abnormality were compared to thevalues obtained for unaffected pregnancies and werefound to be lower.

Lately, much attention has been given to lowerlevels of AFP possibly indicating that the fetus hasDown's syndrome. In cases of levels below 0.5 xMOM, a thorough ultrasonic examination is done toconfirm the calculated gestational age. Only then isamniocentesis considered when the risk for Down'ssyndrome according to the maternal age and weightis greater than 1:250.

MULTIVITAMIN STUDYIn 1985, Israel joined the international studyorganised by the Medical Research Council inEngland for the prevention of neural tube defects(NTD) by preconceptual treatment with vitamins.The Sheba Medical Centre is the Israeli agency andpatients who have had at least one NTD affectedchild/fetus are seen from all over the country forspecial counselling, in which they are encouraged tojoin the project.

FETAL BLOOD SAMPLINGRecently it has become possible to perform fetalblood sampling from the second trimester onwards.The procedure is carried out with ultrasonographicguidance. The indications for the procedure arerapid chromosomal analysis and sex determinationas well as biochemical tests in special circumstances.

Genetic counselling and services

Seven medical genetics centres localised in teachinghospitals affiliated with one of the four medicalschools provide genetic counselling in Israel. Allgenetic centres have laboratory facilities for tissueculture and cytogenetics. Biochemical tests areusually carried out in specialised laboratoriesaccording to the type of test. Most centres coordin-ate the multidisciplinary management of complexsyndromes. Genetic counselling is also given beforeevery prenatal diagnostic procedure for geneticconditions.

In general, the approach to genetic counselling inIsrael is non-directive. A main concern is thepatient's autonomy. In order for this to be respectedand maintained it is felt that all relevant information

should be disclosed even when ambiguous or con-troversial; thus, data and options are presented in anobjective way. The same approach is used regardinggenetic counselling in prenatal diagnosis.

Prenatal diagnosis for sex selection unrelated to Xlinked conditions is strongly opposed by geneticistsin Israel. The main reasons are opposition toaborting a normal fetus, which is seen as morallyunacceptable, and the fact that being of the un-wanted sex is not a medical condition that merits theuse of the limited resources and facilities available inthe genetic centres. On the other hand, prenataldiagnosis is accepted for both maternal anxiety andin women who would oppose abortion. Approxi-mately 3000 prenatal diagnostic tests are performedper year in laboratories of the genetic centrescertified by the Ministry of Health for this purpose.As previously stated, genetic counselling precedesevery procedure. The most common reasons forrefusing an amniocentesis when recommended bythe geneticists are religious objections and maternalanxiety. In approximately 10% of the refusals, thetest is not performed because of the husband'sopposition.The Institute of Medical Genetics at the Sheba

Medical Centre has recently embarked on anextensive programme for evaluating the impact ofgenetic counselling on the processes of coping anddecision making. Hopefully, the results of this studywill teach us new ways to improve our counselling.In addition to this undertaking, it is developing itsown software for the computerisation of all geneticcounselling files.

In 1980, a National Program for the Detectionand Prevention of Birth Defects was established andsponsored by the Ministry of Health. Besidesprenatal diagnosis, it also includes screening ofnewborn infants and of high risk populations.Newborn screening tests include phenylketonuria

(PKU) and hypothyroidism (Guthrie test and T4/TSH). Obviously, newborn infants are also screenedfor congenital malformations in the nursery. Amonitoring system for congenital malformationsexists in four hospitals, accounting for approxi-mately 18 000 births per year (20% of the births peryear in Israel). Israel is a member of the Inter-national Clearing House for Birth Defects Monitor-ing Systems. Recently, a computerised programmefor monitoring birth defects, providing geneticcounselling, and performing epidemiological andclinical research studies has been developed, underthe auspices of the Sackler School of Medicine ofTel-Aviv University. The programme is initiallybeing undertaken in the departments of neonato-logy of three hospitals in the Tel-Aviv area (Hakirya,Beilinson, and Sheba hospitals).

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Boards in Medical Genetics

The Israel Society for Medical Genetics (ISMG) wasformally recognised and its constitution was

accepted by the Israel Medical Association (IMA) inNovember 1986. This confers the status of 'MedicalSpeciality' and obliges members to conform to therules of the IMA. The Israel Department of Healthcan now recognise such specialist status and this has,for the first time, made it possible to request paidposts for medical geneticists, non-medical geneti-cists, and laboratory workers in the public hospitalsystem by way of the Treasury. A syllabus andprogramme for postgraduate study for qualifyingMD medical geneticists has been submitted to theScientific Council of the IMA for approval. Allfuture geneticists and genetics units will requireaccreditation by the ISMG Scientific Council. Pre-liminary ideas on requirements for certificationinclude: after six years undergraduate training, twoto four years of specialist training in any of the othermedical specialities recognised by the IMA but withemphasis on longer periods of clinical experience inpaediatrics, internal medicine, and obstetrics andgynaecology; two years of clinical genetics in an

approved genetics unit; six months of basic sciencetraining in a medical genetics laboratory; andtheoretical requirements in classical genetics, cyto-genetics, biochemical genetics, molecular biology,teratogenesis, clinical syndromology, and geneticcounselling have been delineated. Preparation for afinal theoretical examination will be in the form offormal postgraduate courses to be given at the Tel-Aviv and Jerusalem Medical Schools.

Conclusions

Three historical events set the stage for theflourishing of human genetic studies in Israel: (1)the establishment of the modern State of Israel in1948, (2) the subsequent mass Jewish immigration tothe country from all parts of the world, and (3) thenewly emerging discipline of medical genetics. Forapproximately the past four decades Israeli physi-cians and human geneticists have been studyinggenetic polymorphisms and diseases not only in theJewish but also the non-Jewish communities ofIsrael. As a result of these efforts a wealth ofinformation has been amassed. Regarding theJewish communities, population studies have shownthat, apart from a few exceptions, most of thecommunities differ markedly from their former non-

Jewish host populations. Studies on genetic diseasesin Jews have shown that each of the major Jewishgroups (Oriental, Sephardi, and Ashkenazi) for themost part have their own distinct and characteristicdisorders.

The Israeli genetic community has been stimu-lated, not only by its plethora of material but also bythe current advances being made in all phases ofhuman genetic studies, to continue to increase itsknowledge of genetic diseases and population differ-ences and similarities, and also to improve the careof all its people who suffer from genetic diseases. Abrief account of our current activities has beenpresented in this review. Just as few would havepredicted 40 years ago the scientific advances thathave taken place in the sphere of human genetics, sowe shall be surprised as to the tremendous progressthat will be made in the next 40 years that will resultin better health for all mankind.

Supported in part by grants (to RMG) from theNational Foundation for Jewish Genetic Diseasesand LA-CO Industries in the USA. The authors aregrateful to Mrs Ruth Grossman for her secretarialassistance.

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Correspondence to Professor R M Goodman,Institute of Medical Genetics, The Chaim ShebaMedical Centre, Tel-Hashomer 52621, Israel.



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