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1 X/99/$03.00/0 Vol. 84, No. 12 The Journal of Clinical Endocrinology & Metabolism Printed in U.S.A. Copyright 1999 by The Endocrine Society COMMENTARY Mendelian Diseases among Roman Jews: Implications for the Origins of Disease s CAROLE ODDOUX, ENCARNACION GUILLEN-NAVARRO, CLAUDIO DITIVOLI, ELVIRA DICAVE, MARIA ROBERTA CILIO, C. MARK CLAYTON, HOLLY NELSON, KYRIAKIE SARAFOGLOU, NICOLE MCCAIN, HAVA PERETZ, URI SELIGSOHN, LUCIO LUZZATTO, KHEDOUJA NAFA, MICHAEL NARDI, MARGARET KARPATKIN, IVONA AKSENTIJEVICH, DANIEL KASTNER, FELICIA AXELROD, AND HARRY OSTRER Department of Pediatrics (C.O., E.G-N., C.M.C., H.N., K.S., N.M., M.N., M.K., F.A., H.O.), New York School of Medicine, New York, New York 10016; Universita di Roma La Sapienza (C.D.), Rome, Italy; Ospedale Israelitico (E.D.), Rome, Italy; Ospedale Bambino Gesú (M.R.C.), Rome, Italy; Sourasky Medical Center (H.P.), Tel Aviv, Israel; Institute of Thrombosis and Hemostasis, Department of Hematology (H.P., U.S.), Chaim Sheba Medical Center, Tel-Hashomer, Israel; Department of Human Genetics (L.L., K.N.), Memorial Sloan-Kettering Cancer Center, New York, New York; and National Institute of Arthritis and Musculoskeletal Disorders (I.A., D.K.), National Institutes of Health, Bethesda, Maryland THE JEWISH community in Rome dates from Hasmonean times in the pre-christian era (1). This historically continuous group has been endogamous for much of its 2000-yr history (2). The relatedness of Roman Jews to other Jewish groups is unknown. Contemporary Roman Jews claim to be neither Ashkenazi nor Sephardic, although the historical record suggests that there may have been admixture with both groups during the Middle Ages (3, 4). Conversely, it has also been suggested that Roman Jews may have been the forebears of Ashkenazim (5). One way of tracking the relatedness of Roman Jews to other Jewish groups is to look for the presence of signature Mendelian conditions, each with a characteristic common allele. Many signature Mendelian genetic conditions have Received August 24, Revision received October 12, Accepted October 12, Address correspondence and requests for reprints to: Harry Ostrer, M.D., Human Genetics Program, Department of Pediatrics, New York University School of Medicine, 550 First Avenue, MSB 136, New York, New York harry.ostrer@med.nyu.edu. ABSTRACT The Roman Jewish community has been historically continuous in Rome since pre-christian times and may have been progenitor to the Ashkenazi Jewish community. Despite a history of endogamy over the past 2000 yr, the historical record suggests that there was admixture with Ashkenazi and Sephardic Jews during the Middle Ages. To determine whether Roman and Ashkenazi Jews shared common signature mutations, we tested a group of 107 Roman Jews, representing 176 haploid sets of. No mutations were found for Bloom syndrome, BRCA1, BRCA2, Canavan disease, Fanconi anemia complementation group C, or Tay-Sachs disease. Two unrelated individuals were positive for the C- T cystic fibrosis mutation; one carried the N370S Gaucher disease mutation, and one carried the connexin delT mutation. Each of these was shown to be associated with the same haplotype of tightly linked microsatellite markers as that found among Ashkenazi Jews. In addition, 14 individuals had mutations in the familial Mediterranean fever gene and three unrelated individuals carried the factor XI type III mutation previously observed exclusively among Ashkenazi Jews. These findings suggest that the Gaucher, connexin 26, and familial Mediterranean fever mutations are over 2000 yr old, that the cystic fibrosis kb C- T and factor XI type III mutations had a common origin in Ashkenazi and Roman Jews, and that other mutations prevalent among Ashkenazi Jews are of more recent origin. (J Clin Endocrinol Metab 84: , 1999) been described among Ashkenazi, North African, and Middle Eastern Jews (6, 7). The alleles for each of these conditions may have been present in the founders of the population, they may arise independently after the population was established, or they may have been exchanged through admixture with neighboring populations. Through genetic drift or selection the of some of these alleles has become quite high. When found in more than one population, the common origin of disease alleles can be demonstrated by their association with the same alleles of tightly linked microsatellite markers. Unlike the situation in other endogamous Jewish groups, no signature Mendelian genetic conditions have been described in the Roman Jewish community. To examine the relatedness of Roman Jews to the potentially progenitor Ashkenazi and Middle Eastern Jews and to the potentially descendant Ashkenazi Jews and Sephardic Jews of the Levant, we tested 107 members of the Roman Jewish community for alleles known to be prevalent among each of those groups. 4405

2 4406 ODDOUX ET AL. JCE&M 1999 Vol 84 No 12 Subjects Subjects and Methods Personal and family histories and blood samples were obtained from 107 healthy Roman Jewish volunteers at the Ospedale Israelitico in Rome. All subjects were self-identified as Roman Jewish, and some were members of the same family. Virtually all were known to the study organizers, who recognized them as members of this community. All of the subjects were interviewed by Roman Jewish medical students from the University of Rome La Sapienza Medical School who were trained to administer a structured medical questionnaire. Family histories were taken to assess the genetic relatedness of the subjects and the presence of genetic conditions known to be prevalent among other Jewish populations. To confirm allele frequencies for Tay-Sachs, Canavan and Gaucher diseases, cystic fibrosis, Bloom syndrome, and Fanconi anemia previously reported in our laboratory, or elsewhere, mutation analysis was performed on a group of 1500 Ashkenazi Jews who presented to the Human Genetics Program from January 1998 to June 1999 for testing for one or more of these conditions. The characteristics of this population have been described (8). Genetic analysis DNA was extracted from ethylenediaminetetraacetate-treated blood samples using an FDA-approved commercial kit (Gentra Systems, Minneapolis, MN). Analysis of mutations common among Ashkenazim for Bloom syndrome, breast and ovarian cancer susceptibility (BRCA1 and 2), Canavan disease, cystic fibrosis, factor V Leiden, factor XI deficiency, Fanconi anemia complementation group C, Gaucher disease, nonsyndromic neurosensory hearing loss (connexin 26), and Tay-Sachs disease (Tables 1 and 2) were performed by multiplex PCR and allele-specific oligonucleotide hybridization to specific mutant or corresponding wildtype probes (9 19). Comparison of allele frequencies was performed by 2 analysis. Mutation detection for the common familial Mediterranean fever (MEFV) mutations was performed as described previously (20). Detection of the G6PD deficiency Med1 mutation (for 53 male subjects) and the factor XI deficiency mutations (for all of the subjects) was performed by PCR, followed by restriction enzyme digestion (21, 22). Screening for -thalassemia was performed by measuring mean corpuscular volume using a Coulter counter (Coulter Electronics, Hialeah, FL). Mutation origin studies were performed by analysis of fluorochromelabeled, polymorphic microsatellite markers on an ABI 310 DNA analyzer. These markers included: for glucocerebrosidase, D1S2777, D1S2140, D1S1595, and D1S2721; for CFTR, IVS8CA, IVS17BTA, and IVS17BCA; and for connexin 26, D13S141, D13S175, and D13S250 (18, 23, 24). sizes were determined by comparison with samples from Ashkenazi Jewish individuals previously shown to be heterozygotes or homozygotes for these mutations. For glucocerebrosidase and connexin 26, samples were available from individuals with microsatellite alleles of known sizes. To calibrate the allele sizes for CFTR, PCR products from individuals shown to be homozygous for a particular marker were sequenced using fluorochrome-labeled dye terminators (PE Biosystems, Foster City, CA) and the number of repeats was counted. Results Characteristics of the study population Of the 107 members of the study population, 55 were men and 52 were women. The ages ranged from 17 to 80 yr. Based on the relationships described, 176 haploid sets of were represented. Among 106 individuals who provided information about ethnic origin, 81 indicated that their grandparents had been born in Rome. Of the remainder, 20 indicated that at least one grandparent had been born in Rome, 4 indicated that at least one grandparent had been born elsewhere in Italy, and 1 was of central and eastern European origin. sharing with other Jewish populations Among 107 people tested, three unrelated individuals carried the factor XI type III mutation, two unrelated individuals were positive for the CFTR kb C- T mutation, one carried the glucocerebrosidase N370S disease mutation, one each carried the connexin 26 30delG and 167 delt mutations and 10 carried the factor V Leiden mutation. Of these, all reported to be of pure Roman Jewish origin, except for one factor XI type III carrier who was of mixed Roman and Italian Jewish origin and one factor V Leiden carrier who was of mixed Roman and Sephardic Jewish origin. In addition, 13 individuals had known mutations in the MEFV gene: five E148Q heterozygotes and one homozygote (among 95 tested), two P369S heterozygotes (among 103 tested), three M694V heterozygotes (among 107 tested), and two V726A heterozygotes (among 107 tested) (Table 1). Of these individuals, eight were of pure Roman Jewish ancestry. No individual was found to carry other disease-causing mutations that have been observed in Ashkenazi Jews, including BLM 6 bp-del/7 bp-ins, BRCA1 185delAG and 5382insC, BRCA2 6174delT, N-aspartyl-acylase E285A and Y231X, CFTR deltaf508, W1282X, G542X and N1303K, FAC IVS4DS, A- T, TABLE 1. s found among Roman Jews Disease Gene Mutation Ashkenazi Jews bearing mutation Roman Jews bearing mutation Cystic fibrosis CFTR kb C T Familial MEFV M694V Mediterranean Fever (20) V726A E148Q P369S Factor V Leiden FV R506E Factor XI deficiency FXI F283L (type III) (21) Gaucher disease Glucocerebrosidase N370S Nonsyndromic Connexin 26 30delG deafness (18) 167delT

3 COMMENTARY 4407 TABLE 2. s not found among Roman Jews Disease Gene Mutation Ashkenazi Jews bearing mutation Bloom syndrome a BLM 6 bp-del/7 bp-ins Breast cancer (10, 12) a BRCA1 185delAG insC BRCA2 6174delT Canavan disease a N-apartyl-acylase E285A Y231X Cystic fibrosis a CFTR deltaf W1282X G542X N1303K Fanconi anemia a FACC IVS4DS, A-T, Factor XI deficiency (22) FXI E117X (type II) Gaucher disease a Glucocerebrosidase N370S R496H GG L444P IVS2DS, G-A, Tay-Sachs disease a Hexosaminidase A 4-bp ins, ex IVS12DS, G-C, G269S a Current dataset. the Roman and Ashkenazi Jewish carriers, suggesting a common origin. frequencies among Ashkenazi Jews The allele frequencies for BLM, N-aspartyl-acylase, CFTR, glucocerebrosidase, and hexosaminidase A were determined for a new cohort of Ashkenazi Jews and were compared with those previously reported from our program (8, 12). In every case, no significant difference was found. In addition, allele frequencies were determined for FAC IVS4DS A-T 4, and factor V Leiden in this cohort and compared with those previously reported by others (15, 16, 25). Likewise, no significant differences were found, suggesting that the cohorts of Ashkenazi Jews that we have studied are representative. FIG. 1. Comparison of alleles of tightly linked markers among Ashkenazi and Roman Jewish carriers for the Gaucher N370S, CFTR kb C T, and connexin del T mutations. The allele numbers were derived from those reported previously (18, 23, 24). Note that 1 represents a novel allele. 4, factor XI E117X (type II), glucocerebrosidase R496H, 84GG, L444P, and IVS2DS, G- A, 1, and hexosaminidase A 4-bp ins, ex11, IVS12DS, G- C, 1, and G269S (Table 2). In addition, no individual was found to have the G6PD Med1 mutation nor to have a low mean corpuscular volume, suggestive of a carrier state for - or -thalassemia. Origin of mutations To determine whether the glucocerebrosidase N370S, the CFTR kb C- T, and the connexin delt mutations had a common origin between Ashkenazi and Roman Jews, closely linked and intragenic polymorphic microsatellite repeat markers were typed and compared (Fig. 1). In every case the inferred haplotypes were identical between Discussion The Roman Jewish community is a highly endogamous group in which the members speak Italian and tend to be religiously observant. Of the population sampled, almost 80% indicated that all four grandparents had been born in Rome. In 1965, an even higher proportion of Roman Jews reported that their grandparents had been born in Rome, suggesting that this has been a stable population in recent times (26). Historically, Jews have been present in Rome for over 2000 yr (1). The first settlers date from Hasmonean times in the 2nd century B.C.E. Following the destruction of the Temple in 70 A.D., a large population of Jews was forcibly resettled in Rome. Over the course of the ensuing 2 millennia, this population resisted the secularizing influences of the Roman Empire and subsequently Catholic Italy to retain its identity (2). Sometimes retention of identity was imposed by outside events. Among these events was a Catholic Church ordinance in 1215 requiring Jews to wear a distinctive device on their clothes and the creation of Roman Jewish ghetto in 1558.

4 4408 ODDOUX ET AL. JCE&M 1999 Vol 84 No 12 From its creation, until the time of its destruction in 1870, Jews were required to live within the ghetto. Members of the early Jewish population of Rome migrated to other Italian cities and north of the Alps into France and Germany to create populations that may have become the forebears of contemporary Ashkenazi Jews. In turn, admixture may have occurred over the past 800 yr between the Roman Jewish population and other Jewish groups (3, 4). Jews from France and Germany settled in Italy after their expulsion in the late 13th and early 14th centuries. Following the Spanish Inquisition in 1492, some of the Jews from the Spanish-ruled states of Sicily and southern Italy were taken into Rome, whereas others continued their migration east to the Balkans, Turkey, and the Middle East (27). Over time the Sephardic and Ashkenazi inhabitants of Rome were assimilated into the Roman Jewish community. Internal migration occurred among the Jewish populations of the other Italian states. Since the late 19th century, the combination of internal migration, assimilation, and the Holocaust of the Second World War has led to the marked diminution of all Jewish population centers in Italy, with the exceptions of those in Rome and Milan. Of these, the contemporary Milanese Jewish population has been derived principally from Ashkenazi and Egyptian Jewish immigrants arriving after the Second World War (28). Based on the known historical events, the ancient Roman Jewish community may have been progenitor to Ashkenazim. Conversely, the contemporary Roman Jewish population may have had Ashkenazi forebears. The observations of this study support both possibilities (Table 3). Mutations in connexin 26, MEFV, and glucocerebrosidase previously shown to have a Mediterranean origin are found in both the Roman and Ashkenazi Jewish populations (18, 20, 29). The ages of the glucocerebrosidase and the MEFV mutations have both been estimated to be several thousand years (29, 30). The factor XI type 3 mutation, previously described only among Ashkenazi Jews and shown to have been of fairly recent origin, has now been found among Roman Jews (21, 31). Although the CFTR kb C- T mutation occurs at a known hotspot of mutation, and independent mutations have been previously described among Czechs and Germans, it occurs on the same genetic background among Ashkenazi and Roman Jews, indicating a common origin (32). Indeed, analysis of Y chromosomal haplotypes supports the notion of a close degree of relatedness among the Roman and Ashkenazi Jewish populations (Oddoux, C., Ostrer, H., Hammer, M., unpublished observations). Further refinement about the ages of these mutations in the Roman and Ashkenazi Jewish populations (which could only be undertaken with the discovery of many carriers or homozygous affected individuals in the Roman Jewish population) would serve only to resolve that specific question, without providing further insight about which population was progenitor. This study is unable to answer the issue about the relatedness of Roman Jews to Sephardic Jews. The only Mendelian conditions that occur with measurable frequencies among the Sephardic Jews of the Levant are familial Mediterranean fever, -thalassemia, and G6PD deficiency from the Med1 mutation (Table 3) (20, 33 35). Familial Mediterranean fever mutations have been shown to be panethnic among Jewish populations and, thus, are uniformative for judging admixture with Sephardim (20). -Thalassemia is genetically heterogenous among Jewish populations (33). The absence of thalassemia carriers did not provide a basis for searching for specific mutations. The absence of the G6PD Med1 mutation was unanticipated given the high frequencies of this mutation among Jews of Sephardic and Middle Eastern origin, the reported historical admixture of Roman and Sephardic Jews, and the fact that selection for G6PD Med1 occurred in Italy until fairly recent times (34, 35). The absence of G6PD Med1 among the Roman Jews parallels the low found among Ashkenazi Jews, favoring common origin and/or admixture of these two populations. In view of the fact that the historical record suggests that Ashkenazi Jewish admixture into the Roman Jewish population occurred from the Middle Ages onward, it is surprising that the highly prevalent nonclassical CAH mutation is not found in the Roman Jewish population (36). The allele TABLE 3. Population distribution of discriminating alleles Non-Jewish Mediterranean people Roman Jews Ashkenazi Jews Sephardic Jews Iraqi Jews G6PD Med1 Cx26 delt FXI-Type 2 GD-N370S CFTR kbC T a FXI-Type 3 21-OH CAH BRCA1 185delAG BRCA delt FAC IVS4DS A-T 4 BLM TS-4bp ins CFTR W1282X CD-E285A CD-Y231X Table shows population distribution of discriminating disease alleles found at a of 1 in 500 or more in at least one of the populations shown and that does not occur uniformly in all of the populations sited. a Mutation occurs on different haplotypes in different populations, indicating independent origins of the mutation in each population. The mutation found in the Roman Jews occurs on the same haplotype background as that found in the Ashkenazi Jews, indicating a common origin.

5 COMMENTARY 4409 of this mutation has been observed to be 17.3% among Ashkenazi Jews (37). These observations suggest that this allele may have arisen following the migration of Jews out of Italy and into northern Europe. In view of the fact that the of this allele is some five to six times higher that other common recessive alleles, the contemporary frequencies of which are thought to have been influenced by genetic drift, it is quite possible that the high of the nonclassical 21-hydroxylase gene may have been influenced by selection. The occurrence of this mutation in linkage disequilibrium with a specific histocompatibility leucocyte antigen haplotype suggests a mechanism by which this selection may have occurred (38). Similarly, other populationspecific and relatively common mutations among Ashkenazi Jews, including BLM 6 bp-del/7 bp-ins, BRCA2 6174delT, N-aspartyl-acylase E285A, CFTR W1282X, FAC IVS4DS A- T 4, and hexosaminidase A 4-bp ins ex11, were not found among the Roman Jews, supporting the idea that these mutations were recent in their origin. This study is the first report of Mendelian genetic conditions among the Roman Jews, and, thus, has clinical implications for this population. Assuming that these genes are in Hardy-Weinberg equilibrium, the frequencies with which people with these conditions may be found in the Roman Jewish community are 1:10 for factor V Leiden, 1:96 for familial Mediterranean fever, 1:3,600 for factor XI deficiency, 1:1,792 for nonsyndromic hereditary deafness, 1:7,744 for cystic fibrosis, and 1:30,976 for Gaucher disease. 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