Molecular Basis of Mendelian Disorders among Jews

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    Molecular Basis of Mendelian Disorders among Jews

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    Molecular Genetics and Metabolism 69, 169180 (2000)doi:10.1006/mgme.2000.2969, available online at onand way of life, in their spoken language,their traditions. While differences existedthe various regions where the Ashkenazi

    ere living, there are no true subgroupshem. On the other hand, most of the Orien-Sepharadic Jewish communities remainedhically separated and developed as distinct

    of the community as well as the relative advance inmedicine in the countries in which they lived. Soonafter the foundation of the state of Israel many phy-sicians, in particular, the late Haim Sheba and thelate Richard Goodman, initiated studies on geneticdiseases among the various Jewish communities (3).Since then, the molecular bases of most of the dis-

    1691096-7192/00 $35.00

    Copyright 2000 by Academic PressAll rights of reproduction in any form reserved.Joel Zlotogora,* Gideon Bach, a

    *Department of Community Genetics, Ministry of HealthHadassah Medical Center, Hebrew University, J

    de Genetique, Hopital Necker-Enfants

    Received November 22, 1999, and in rev


    ewish people originate from the Middle East.e destruction of the First Temple, part of theity remained in Palestine while another

    oved eastward founding the Babylonianncestors of the Iraqi and Iranian Jews. Withof the GrecoRoman empires, Oriental Jewso move also westward as far as Spain andl, where a large Jewish community devel-the Middle Ages. Sephardic Jews (from theword for an area often identified with Spain)endants of the Jews who were forcibly ex-uring the Inquisition in Spain and settledn the countries along the Mediterranean Seahe Netherlands and the New World.ajor movement of Oriental Jews toward

    Europe was in the Middle Ages to Francermany. Later, there were two importantf migrations of the Ashkenazi Jews (from aaning Germany) in central Europe: the first

    5th16th century eastward to Bohemia andlly to PolandLithuania and then from thehe 18th century back to the west (Germany,ands, England, United States).



    Teasrnold Munnich

    el; Department of Human Genetics,m, Israel; and Departement

    des, Paris, France

    rm January 22, 2000

    s. Therefore, a more useful classification of-Ashkenazi Jews is one using their country/f origin together with the community theyom. While the non-Ashkenazi communitiested more than 90% of the Jews in the 12th

    , because of the size expansion of Ashkena-y represented only 10% of the world Jewry. Today, the estimated number of Jewsde is 1314 million, some 75% of whom areenazi origin. In 1996 there were 4.6 millioning in Israel, 50% of whom were of Ash-rigin (1).consanguineous marriages are allowed inish religion, they were common in all theities, including the Ashkenazi Jews. In a

    n Israel after the foundation of the State theuinity rate varied from 1.4% among Ash-ews to 28.7% among Jews from Iraq (2). In

    t decades intercommunity marriages havere and more frequent, and within each of theities consanguineous marriages have beeng rapidly (T. Cohen, personal communica-

    rst observations that various genetic dis-e relatively frequent among Jews were made

  • orders have been elucidated and many of the muta-tions identified (Table 1).

    Some of the disorders, such as thalassemia, famil-ial Mediterannean fever, and G6PD deficiency,which aamongfrequenever, thefrequenJews. Aders areseverallimited

    At theof the 2emigratthe AmMost ofin Europthe warToday,are in tditionalUkrainezil, and

    Genetkenazimoleculmutatioalleles apresent.which on


    Bloomthe disepresent,are raresyndromthe sevand thepatientssyndromunique m(4,5). Inerozygotrespecti


    tions and is the only other disorder present almostexclusively among Ashkenazi Jews. The gene wasmapped to 9q31q33, and the strong linkage dis-equilibrium found among the Ashkenazi Jewish pa-

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    170 ZLOTOGORA, BACH, AND MUNNICHre found with a relatively high frequencysome of the Jewish communities, are alsot in the non-Jewish local population. How-se are exceptions and in most cases the high

    cy of the genetic diseases is particular to themong the Jewish people, some genetic disor-

    found with a relatively high frequency incommunities, but often the high frequency isto one single community.


    end of the 19th century and the beginning0th century, there was an important Jewishion from central Eastern Europe mainly toerican continent, South Africa, and Israel.the Ashkenazi Jewish community remaininge was decimated in the Holocaust, and aftermany of the survivors immigrated to Israel.

    the largest Ashkenazi Jewish communitieshe United States and in Israel. Several ad-large Ashkenazi communities are in Russia,, Canada, United Kingdom, Argentina, Bra-South Africa.ic disorders relatively frequent among Ash-Jews may be separated according to theirar basis into two groups: those in which onen is found in more than 95% of the diseasend those in which multiple mutations areWithin the second group is a subgroup ine of the multiple mutations is predominant.

    rs in which One Mutation Is Found

    syndrome and Fanconi anemia. Amongases in which a single major mutation isboth Bloom syndrome and Fanconi anemiaeven among the Ashkenazim. In Bloom

    e the most prominent clinical symptoms areere pre- and postnatal growth retardationunusually high rate of neoplasia. Most of thereported in the world affected with Bloome are Ashkenazi Jews, and among them autation, [BLM, 6-BP del/7-BP ins], is foundpopulation studies, the frequencies of het-es for this mutation were 1:107 and 1:231,vely (6,7).

    ial dysautonomia is a disease due to a dis-e of autonomic and peripheral sensory func-


    Fmo50SoJewmaenG1is pJew(10



    LstoAsNidisEaoflismtiemuwetiotantheG2allSafouJewinaothL4Nisimmuems to point to a founder mutation (8,9).

    ial hypercholesterolemia, a relatively com-etic disorder in the general population (1:

    found with a much higher prevalence amongfrican Jews (1:67). Most of the South Africancommunity originated from East Europe,ithuania, and settled in South Africa at the

    the 19th century. The mutation [LDLR,l] probably originated from a founder since itnt not only in South African Jews but also iniginating from Lithuania living in Israel

    thic torsion dystonia of early onset is un-nce a unique recurrent 3-bp GAG deletion ofe DYT1 is present in all the patients irre-

    of their origin. However, among the Ash-ews more than 90% of the patients have ahaplotype pointing to a common origin,as probably relatively recent (350 years)

    rs Caused by Multiple Mutations

    omal storage diseases. Three lysosomaldiseases are relatively frequent among thezi Jews, namely, TaySachs disease,

    nPick-type disease type A, and Gaucherwhich are caused by multiple mutations.

    these disorders is secondary to the deficiencyerent key lysosomal enzyme in the catabo-phingolipids. Among Ashkenazi Jewish pa-

    ffected with TaySachs disease three majorns in the a subunit of b-hexosaminidaseentified (13). The two most frequent muta-e [HEXA, 4-BP ins, EX11] (73% of the mu-les) and [HEXA, IVS12 1 1G3 C] (17.6% of

    tant alleles). The third mutation, [HEXA,which is relatively rare (3.5% of the mutantis responsible for the adult type of Tay

    isease. In the adult type of Gaucher disease,tations are found in most affected Ashkenazipatients but one, [GBA, N370S], is predom-d present in 85% of the patients (14). The

    utations are rarer, [GBA, 84GG] (6%), [GBA,(3.5%), and [GBA, IVS2, 11G3 A] (1%). FornPick disease type A, three mutations withfrequency account for more than 95% of thealleles found among Ashkenazi Jewish pa-

  • TABLE 1

    Disorder MIM InheritanceHeterozygote

    frequencyMolecular basis: gene and major

    responsible mutations

    Ashkenazi Jews

    Abetalipoproteinemia 200100 AR Rare MTPAdrenal h

    OH defiBloom synBreast/ova

    Canavan dColon canCystic fibr

    DeafnessDysautonoFactor XIFamilial MFanconi aGaucher dGlycogenoGlycogeno




    Torsion dy

    Adrenal hhydroxy

    Albinism,Ataxia telColor blinComplemeCystinosisCerebroteFactor VIIFamilial MGlycogenTaySach

    Brittle corFactor V aFamilial MFragile XSelective i


    CreuzfeldCystinuriaLimb girdFamilial M

    171MOLECULAR BASIS OF MENDELIAN DISORDERS AMONG JEWSyperplasia III nonclassical 21ciency

    201910 AR 1:10 CPY21

    drome 210900 AR 1:231 BLM [6-BP del/7-BP ins]rian cancer (predisposition) 113705 AD 1:100 BRCA1 [185delAG]; BRCA1 [5382insC];

    600185 AD 1:75 BRCA2 [6174delT]isease 271900 AR 1:59 ASPA [E285A]; [Y231X]

    cer (predisposition) 175100 AD 1