HUMANMUTATION 28(10),944^949,2007

DATABASES

Documentation of Inherited Disordersand Mutation Frequencies in the DifferentReligious Communities in Israel in the IsraeliNational Genetic Database

Joel Zlotogora,1 Sjozef van Baal,2 and George P. Patrinos2�

1Department of Community Genetics, Public Health Services, Ministry of Health, Ramat Gan, Israel; 2Medical Genetics Cluster (MGC)Department of Cell Biology and Genetics, Erasmus University Medical Center, Faculty of Medicine and Health Sciences, Rotterdam,The Netherlands

Communicated by Alastair Brown

The National and Ethnic Mutation Databases (NEMDBs) are continuously updated mutation depositories thatcontain extensive information on the described genetic heterogeneity of an ethnic group or population. Here,we report the construction of the Israeli National Genetic database (Available at: www.goldenhelix.org/israeli;Last accessed: 20 April 2007) to document the sheer genetic heterogeneity found in the Jewish and non-Jewishpopulations in Israel. The database is built and maintained online using a newly developed customized versionof the ETHNOS platform. The Israeli NEMDB is the richest in information among individual NEMDB,containing summaries of 347 genetic disorders studied for the Israeli populations with numerous relevantreferences and links to the respective Online Mendelian Inheritance in Man (OMIM) entries. Summaries canbe selected from an alphabetical summary index or queried using a keyword-based search functionality. An easy-to-use query interface provides access to the over 600 entries on allelic and carrier frequencies of the differentmutations responsible for certain inherited disorders in the Jewish and non-Jewish populations, although suchdocumentation is not as extensive as in the other ETHNOS-based NEMDBs. Also, the Israeli NEMDB providesa comprehensive listing of all laboratories providing molecular genetic testing services in Israel with a separatequery interface for the user to select which genetic service is provided to a certain laboratory. The IsraeliNEMDB is a useful user-friendly and extendable online resource for genetic services in Israel, while themodified version of the ETHNOS software can be particularly useful for similar projects in other populations.Hum Mutat 28(10), 944–949, 2007. rr 2007 Wiley-Liss, Inc.

KEY WORDS: database; Israel; Jewish; non-Jewish; genetic services; inherited disorders

INTRODUCTION

The National and Ethnic Mutation Databases (NEMDBs) arecontinuously updated mutation depositories, recording extensiveinformation over the described genetic heterogeneity of an ethnicgroup or population. These resources have recently emerged,mostly driven by the need to document the varying mutationspectrum observed for any gene (or multiple genes) associated witha genetic disorder, among different population and ethnic groups.NEMDBs are particularly beneficial: they help to optimize nationalmolecular diagnostic services, assist with the interpretationof ambiguous diagnostic test results in countries with heterogeneouspopulations, and contribute to the elucidation of the origin andmigration of populations and of the recent microevolutionof human populations via precise ethnic identification.

In general, the NEMDBs available to date can be divided in twosubcategories. The ‘‘National Genetic’’ (or Disease Mutation)databases, the first ones that appeared online, record the extantgenetic composition of a population or ethnic group but with limitedor no description of mutation frequencies. Based on the aforemen-tioned criteria, there are five fully-functional NEMDBs that fall

under this banner (Table 1). On the other hand, the ‘‘NationalMutation Frequency’’ databases provide comprehensive informationonly of those inherited disorders whose disease-causing mutationspectrum is well defined. At present, all National MutationFrequency databases, namely Hellenic [Patrinos et al., 2005],Cypriot, Iranian [Kleanthous et al., 2006], Lebanese [Megarbaneet al., 2006], and Serbian (Dragica Radojkovic, Sonja Pavlovic,George P. Patrinos, unpublished results) are derived from theimplementation of the ETHNOS flat-file database software and are,

Published online10May 2007 inWiley InterScience (www.interscience.wiley.com).

DOI10.1002/humu.20551

Received 5 January 2007; accepted revised manuscript 2 April2007.

Grant sponsor: Asclepion Genetics; European Commission FP6INCOMPC3; Grant number: 31968.

�Correspondence to: George P. Patrinos, MGC-Department of CellBiology and Genetics, Erasmus MC, Faculty of Medicine and HealthSciences, POBox 2040,3000 CA, Rotterdam,The Netherlands.E-mail: g.patrinos@erasmusmc.nl

rr 2007 WILEY-LISS, INC.

therefore, uniformly presented with respect to content. However, allNational Genetic databases are built using relational databasemanagement platforms and have diverse format and contents.

Here, we report the construction of the Israeli National Geneticdatabase (www.goldenhelix.org/israeli), a freely available onlineresource for genetic services in Israel. This database has resultedfrom a customized version of the ETHNOS software, adapted toaccommodate large datasets and to support both menu- and keyword-based queries. The Israeli NEMDB is a useful online resource forgenetic services in Israel and the modified ETHNOS software can bea potentially useful platform for the creation and management ofsimilar NEMDBs for other genetically heterogeneous populations.

DEMOGRAPHICS OF THE ISRAELIPOPULATION GROUPS

The Jewish people originated from the Middle East and havebeen dispersed around the world. With the creation of the state in1948, many of the Jews immigrated to Israel. According to theirorigin, the Jews are usually distinguished in several groups, thelargest being the Ashkenazi Jewish community that lived in centralEurope. The other communities are often referred to as Sephardicand Oriental Jews; however, a better delineation is based on thecountry of origin. In 2005 there were more than 5.5 million Jewsliving in Israel, approximately 55% of them being of Ashkenaziorigin. The North African Jews are the second largest community,representing 20% of the Israeli Jewish population; 70% of themoriginated from Morocco. Smaller communities include the Jewsfrom Iraq (7%), Yemen (4%), Iran (4%), and Ethiopia (2.5%). In2005, Israel’s non-Jewish population includes the followingreligious groups: Muslim Arabs (1,140,600), Arab Christians(118,200), Druze (115,200), and non-Arab Christians (27,800).

Consanguineous marriages existed in all the Jewish communities,and after the foundation of the State the consanguinity rates variedfrom 1.4% among Ashkenazi Jews to 28.7% among Jews from Iraq[Goldschmidt et al., 1960]. In the last decades intercommunitymarriages are more and more frequent, and within each of thecommunities consanguineous marriages are declining rapidly [Cohenet al., 2004]. Consanguineous marriages are frequent among Arabsand Druze, more than 40% of the marriages are between relatives,50% of which are between first cousins [Jaber et al., 1994, 2000].The highest consanguinity rates have been observed in the Bedouinsfrom the Negev (60%) [Cohen et al., 2004].

Most of the Arabs and Druze in Israel are living in villages ortribes, which were founded by a few individuals less than 10generations ago, and often include less than 10,000 inhabitants.

GENETIC SERVICESAND INHERITEDDISORDERS IN ISRAEL

Medical Genetic services are organized in independent units intwo private and 15 public hospitals. For relatively frequent genetic

disorders, molecular genetic testing services are offered in severalinstitutes (see also below). Since 1980, a national carrier-screeningprogram for Tay-Sachs and b-thalassemia is offered free-of-chargein the communities in which the diseases are frequent. In the lastdecades a private carrier screening that is partially funded byhealth insurance is offered by the genetic units for fragile-X andcystic fibrosis, as well as other severe diseases, according to theorigin of the families. All of the Israeli population has access to theavailable genetic services that are included in the basketof services offered by the National Health insurance; regardlessof income, origin, health status, age, or long-term need. A detaileddescription on the status of genetic services in Israel has beenpreviously published by Chemke and Zlotogora [1997].

Medical Genetics has been recognized as a medical specialty bythe Israeli Medical Association and the Ministry of Health since1986. Finally, the National Laboratory for the Genetics of IsraeliPopulations (Tel Aviv University) established an Israeli popula-tions DNA and cell-line bank (www.tau.ac.il/medicine/NLGIP),representing a national repository for human cell-lines and DNAfrom the Israeli populations. The first observations that variousgenetic diseases are relatively frequent among Jews were madeamong Ashkenazi Jews [Goodman, 1979]. Since then themolecular basis of many of the frequent disorders have beenelucidated and most of the mutations were identified. Most of therelatively frequent inherited disorders occur at high frequencies inonly one of the Jewish communities, few are found in more thanone community [Zlotogora et al., 2000].

Many genetic diseases also have been reported in the non-Jewish population in Israel. Some are frequent in the entirepopulation and in the Mediterranean region, such as thalassemiaor familial Mediterranean fever (FMF) and Gap Junction ProteinB2 (GJB2) related deafness. However, most of the diseases arefound to be relatively frequent in a local community only. In mostof the cases the high frequency is limited to a village or a Bedouintribe (Zlotogora, 1997).

DATA SOURCES, DATABASECONTENTS,ANDACCESS

Data Sources

Israeli NEMDB data came from compilations of geneticdisorders in Israel that were first published in 1998 and havebeen constantly updated since then; this data has been availableonline since 2002 (Zlotogora, 2007). This information wasconverted to a database, so that new entries could be added andold entries corrected by dedicated advisors. New data are eithercollected from the published literature or contributed directly tothe database curators. In the latter case, data submissions arechecked for consistency prior to being entered into the database.Old entries are periodically checked for consistency and correctedwhere needed. Database updates take place on a monthly basis

TABLE 1. Information andBasic Features of theCurrentlyAvailableNationalGenetic Databases, Deducted FromTheir Source

Database URL Platform Records Querying References

Iranian http://www.ihmd.hbi.ir/about.htm Relational database 415 Key words UnpublishedSingaporean http://shmpd.bii.a-star.edu.sg Relational database 355 Key words Tan et al. [2006]Finnish http://www.¢ndis.org Relational database 67 Key words Sipila andAula [2002]Araba http://www.cags.org.ae/ctga_search.html Relational database 650 Key words Tadmouri et al. [2006]Israeli http://www.goldenhelix.org/israeli ETHNOSV1.2b 974 Menus and

key wordsThis paper

aTheArabNational Genetic database refers to theCenter of ArabGenome Studies resource in theUnitedArab Emirates. A similar resource, namely theArabGenetic Disease database, previously reported [Teebi et al., 2002], is presently discontinued.bFlat-¢le database.

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Human Mutation DOI 10.1002/humu

and the date of the last update is indicated at the main menu.Where available, mutation frequency data are contributed to theFINDbase (www.findbase.org) database of mutation frequenciesworldwide [van Baal et al., 2007]. All aspects of the supplied datawere peer-reviewed and manually curated to ensure consistency,full coverage, and concordance to mutation nomenclaturerequirements [Antonarakis et al., 1998]. Details of data sourcesare provided at the end of each summary page.

Database Contents

The primary goal behind the design of the Israeli NEMDBs wasto ensure a user-friendly environment and query interface. Wehave, therefore, decided to implement the ETHNOS software[Patrinos et al., 2005], as the core database engine. The ETHNOSsoftware is a flat-file database management system, which wasspecifically developed to allow uniform NEMDB construction andcuration. This software has initially supported the construction offive different NEMDBs [Patrinos, 2006]. However, to fulfill therequirements of the existing datasets related to the geneticdisorders of the Israeli populations, the software has been modifiedto cope not only with easy and secure (password-protected) dataentry, storage, and curation of the large datasets requiringdocumentation, but also to address a number of novel featuresthat would make the database appeal to a larger user group. It isnoteworthy that the ETHNOS software, upgraded for theconstruction of the Israeli NEMDB, has maintained its flat-filedatabase management functionalities and is different from the onesupporting the FINDbase operation, which is MySQL-based(www.mysql.com; Uppsala, Sweden) and has relational, and hencemore advanced, database management properties. Nevertheless,although the rest (non-ETHNOS-based) of the NEMDBs areoperating using a relational database management system[Patrinos, 2006] (see also Table 1), they lack a number of featuresincluded in the much simpler flat-file ETHNOS software,supporting the Israeli NEMDB (see also below).

The main menu of the Israeli NEMDB is shown on the left ofeach page, summarizing the database contents, and each selectedpage is highlighted. The Israeli NEMDB has been developedaccording to the religious origin of the population sinceinterreligious marriages are rare and the frequency of the diseasesis very different for each of the communities. The databasecontains 373 summaries regarding 147 inherited disorders found inthe Jewish population and 226 in the non-Jewish population(December 2006 release), making this resource the richestindividual NEMDB currently available (Table 1). These summariesare available in the ‘‘Summary’’ page, are indexed alphabetically,and contain a brief description of the genetic disorder, itsincidence in the Israeli population, link(s) to the respectiveOnline Mendelian Inheritance in Man (OMIM) entry(ies), andreferences.

Also, mutation allelic and carrier frequency data are documen-ted in 622 records, of which 272 records correspond to the Jewishpopulation and 350 to the non-Jewish population, including a totalof 2,102 chromosomes analyzed (March 2007 release). In themajority of cases, the mutation is a founder mutation and onlyobserved either in one Jewish group or, in certain cases in the non-Jewish population, the mutation is limited to either one or twovillages, a tribe, or a wider geographical region. The size of villagesand tribes is usually between 1,000 and 15,000 inhabitants, while aregion includes several villages/towns not far away one from theother. When the carrier frequency appears in parentheses, itrepresents the frequency in this particular village/tribe/region.

Contrary to the wealth of information regarding the incidenceof inherited diseases in Israel, there is relatively limited descriptionof the well-defined mutation frequencies, namely for only 12genetic disorders, seven of which are studied for the Jewishpopulation and five for the non-Jewish population.

Finally, the Israeli NEMDB fulfills all the required qualitycriteria, by including copyright and disclaimer notices and the datewhen the resource was last updated, while all mutation entriescomply with the official Human Genome Variation Society(HGVS; www.hgvs.org) nomenclature.

DatabaseAccess

The Israeli NEMDB can be accessed on the World Wide Web atthe URL address: www.goldenhelix.org/israeli. Detailed instruc-tions for both using and querying the database are also availablefrom the same site. Database access is free-of-charge for allinterested parties. This compilation and representation of it aresubject to certain copyright policies, especially designed to ensurethat this resource remains freely available to all interestedindividuals. Users should bear in mind, however, that the IsraeliNEMDB is designed to work exclusively on modern browsers, suchas MS-Internet Explorer V6.0 or later, etc, and the use of olderinternet browsers may be problematic.

QUERYING THEDATABASESummary and Mutation Data Query

The Israeli NEMDB is equipped with a keyword-based querymodule allowing the user to formulate keyword-based queries inthe disease summaries, to better explore the variety and depthof information recorded therein.

In addition, the typical ETHNOS-based NEMDB mutationfrequencies query module is also present in the Israeli NEMDB,allowing the user to filter the data according to the available(drop-down) menus, namely ‘‘Population,’’ ‘‘Ethnic group,’’‘‘Disorder,’’ and specify the desired ‘‘Mutation frequency’’ range.Results are returned in tabular format, in which the gene andmutation is given in their official nomenclature, accompanied bythe allelic and carrier frequencies, where available, and therespective OMIM ID, hyperlinked to the corresponding web page.

A characteristic sample query is shown in Figure 1, and aims toretrieve all mutations and their frequencies leading to cysticfibrosis in all ethnic groups in the non-Jewish population. Allelicfrequencies are calculated for the non-Jewish population in totaland not individually per ethnic group, and the number of theuncharacterized chromosomes is also shown.

Laboratory Information Query

A useful option that was introduced in the Israeli NEMDB is the‘‘Lab info’’ page, containing all relevant information of theavailable laboratories involved in the provision of genetic servicesin Israel. The user can select the desired genetic laboratory fromthe corresponding table, categorized by Institute, Department, andcity where located (Fig. 2B). Alternatively, the user can select aninherited disorder from a menu, to identify which laboratory isinvolved in the provision of this test (Fig. 2A). In many cases, suchas cystic fibrosis or autosomal sensorineural deafness, more thanone laboratory provides a particular genetic test. The name of theDepartment is hyperlinked to detailed information, includingcontact details, the name of the scientist(s) in charge, and thecomplete list of genetic tests offered by this center. The list oflaboratories and the tests provided is updated regularly bycontacting the scientist(s) in charge (Fig. 2C).

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DATABASECURATION ANDMAINTENANCE

The Israeli NEMDB is administrated locally by Professor JoelZlotogora and his team in Israel, who handles data collection,evaluation for consistency, and correct mutation nomenclatureusage. This team is also responsible for encouraging datacontribution from various sources, in order to increase the impactof this resource. The actual database is hosted in the Golden HelixServer (www.goldenhelix.org) in Rotterdam, the Netherlands, andadministrated by a dedicated bioinformatics team. Data entry anddatabase curation can be maintained online through a dedicatedIP-based and password-protected admin module, from which theadministrator can access the database contents for modification orupdate (Sjozef van Baal, unpublished results).

Due to its large data content, database construction requiredfull-time employment for a 4-month period. Considering thecurrent data input and curation, only part-time employment, inclose contact with the database board of curators is required, andis financially supported by two European grants and privatefunding. This is particularly important in a time when fundingof such projects is gradually becoming more and more difficultto secure [Patrinos and Brookes, 2005].

DATA AND SOFTWARE AVAILABILITY

All Israeli database data are freely available for academicresearch purposes, and data and accompanying descriptions andsoftware are available from www.goldenhelix.org. Researchersinterested in implementing the customized ETHNOS (V1.2)software for their own purposes are encouraged to contact the

administrators (detailed information can be found at the databasewebsite).

COMPARISON BETWEEN THE ISRAELI NEMDBANDTHEOTHER NEMDBS

As explained above, there are several new elements which makethe Israeli NEMDB not only different from the previously launchedETHNOS-based NEMDBs but also to the rest of the NationalGenetics databases. These functionalities have been introduced tothe flat-file ETHNOS database management software, demonstrat-ing its versatility, despite the fact that the system itself is relativelysimple in nature. First, the Israeli NEMDB has two differentquerying interfaces, allowing the user not only to filter mutationfrequency data, which by definition are described on a limited basisin this resource, but also a keyword search module to query theplethora of disease summaries. Such features are present in only afew locus-specific databases, particularly the most comprehensiveones [Claustres et al., 2002], such as HbVar Database of HumanHemoglobin Variants and Thalassemia Mutations (HbVar; http://globin.bx.psu.edu/hbvar) [Hardison et al., 2002; Patrinos et al.,2004; Patrinos and Wajcman, 2004] and the PhenylalanineHydroxylase Locus Knowledgebase (PAHdb; www.pahdb.mcgill.ca)[Scriver et al., 2003]. Also, the large number of inherited disordersavailable dictated the restructuring of the summary page with analphabetical disease summary index rather than a straightforwardlisting. This required software modifications, also necessary toenhance security during data entry [Giardine et al., 2007] (Sjozefvan Baal, unpublished results).

FIGURE 1. Formulationof the query ‘‘Find allelic andcarrier frequencies of all cystic ¢brosismutations in all ethnic groups of theNon-Jewish population.’’ The user needs to select ‘‘Non-Jewish’’ from the‘‘Population’’menu,‘‘All ethnic groups’’ from the‘‘Ethnic group’’menu and ‘‘Cystic Fibrosis’’ from the‘‘Disorders’’menu, and, optionally, de¢ne the desired allele (not carrier) frequency.Query outputis tabulated according to ethnic groups.Where allelic frequency information is not available, these alleles do not participate in thecalculationof allelic frequencies (e.g., p.C2024T found in several families inArabs in the non-Jewish population).TheOMIMcolumnprovides direct links to the respectiveOMIM entry(ies) and gene andmutation names are o⁄cially named.

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The most important element, currently lacking in any NEMDB,is the comprehensive listing of genetic laboratories, together withthe genetic tests they provide. At the moment, Orphanet(www.orpha.net), the European Directory of DNA DiagnosticLaboratories (EDDNAL; www.eddnal.com), and GeneTests(www.genetests.org) [Pagon et al., 2002] provide such servicesfor Europe and the United States, respectively, but in all theseresources the Israeli-specific information is less comprehensive andin certain cases slightly outdated.

CONCLUSION AND FUTURE ASPECTS

NEMDBs are becoming increasingly important for the provisionof genetic services and documentation of population ‘‘genography’’[Patrinos, 2006]. The ETHNOS database platform, exclusivelydesigned to facilitate the construction of NEMDBs, has con-tributed to the promotion of the establishment of similar databases

from different countries and also to database uniformity, as morethan half of the available NEMDBs are based on this platform. Thecustomization of the ETHNOS software for the needs of the IsraeliNEMDB demonstrates the versatility of the platform, whichalthough simple in nature, e.g., based on flat-files, can accom-modate large data sets, without jeopardizing the overall queryprocessing time and data retrieval. It also shows that the softwarecan be easily modified to accommodate the needs of a differentpopulation. Disadvantages of the Israeli NEMDB can beconsidered to be the flat-file platform, if data influx is substantiallyincreased, and the lack of a direct online submission tool,restricting this task to the central database administration group.These issues, if such need arises, can be easily tackled, byupgrading the Israeli NEMDB to the ETHNOS V2.0 MySQL-based relational database platform, which currently empowersFINDbase and FINDbase-related databases [van Baal et al.,2007].

FIGURE 2. Overview of the Israeli NEMDB ‘‘Lab info’’page, listing the available laboratories involved in the provision of genetic ser-vices in Israel. A: A simple query interface allows theuser to ¢lter those laboratories providinggenetic testing services for a particularinherited disorder. B: List of all available laboratories providing molecular genetic testing in Israel and the cities located.The nameof the laboratory is hyperlinked to detailed laboratory information (C), such as the address, contact details, scientists in charge, andthe entire list of genetic tests provided, alongwith the genetic defects screened for.The standardETHNOS sidemenu is always visibleat the left side of the screen, enriched by the‘‘Lab info’’option, currently highlighted.

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In recent decades, immigration has been frequent and theindividuals in their new location tend to live as an isolatedcommunity. The existence of databases on genetic diseasesaccording to population origin will facilitate genetic diagnosisand counseling for those families. As for the Israeli NEMDB, in thecase of the Jewish population the data are relevant for Jews livingoutside of Israel and representing some 50% of the world’s Jewishpopulation. Similarly, a large part of the Palestinian population isliving outside of Israel and much of the information on thefrequent genetic diseases and the mutations responsible may berelevant to that population.

Future developments include the release of the complete list ofmutation information on a quarterly basis as file downloads. Also,user satisfaction surveys will be posted on a regular basis togetherwith questionnaires for information updates. In addition, thedatabase will be linked to the site of the department of communitygenetics, in which most of the other relevant informationpertaining to genetic services in Israel is available in Hebrew, sothat this resource becomes a ‘‘one-stop’’ online resource for geneticservices for the Israeli population. To better achieve these goals,active pursuit of additional funding sources will be necessary,despite the fact that financial viability of this project is ensured forthe next 2-year period.

In essence, the Israeli NEMDB is a useful resource for geneticservices in Israel and can potentially pave the way for the launch ofsimilar projects in different populations. Transformation of theHellenic and Lebanese NEMDBs [Patrinos et al., 2005; Mega-rbane et al., 2006] into National Genetic databases using theETHNOS V1.2 platform is currently ongoing; in the HellenicNEMDB, this work is under the auspices of the HellenicAssociation of Medical Geneticists. Also, the implementation ofthe same platform within the European Commission InternationalCooperation for Mediterranean Partner Countries (INCO MPC3)consortium partners to build separate NEMDBs for the respectivepopulations is currently under consideration. Finally, as user inputis vital for improving database quality and data accuracy, we invitedatabase users to share their thoughts over this resource and tonotify the administrator and database advisors for any oversight ordeficiencies, so that the Israeli NEMDB remains as accurate,complete, and up-to-date as possible.

ACKNOWLEDGMENTS

This work was supported by an FP6 INCO MPC3 grant (31968)to J.Z.

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