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c o m m e n ta r y
Collaborative genomics for human health
and cooperation in the Mediterranean region
Tayfun Özçelik, Moien Kanaan, Karen B Avraham, Drakoulis Yannoukakos, André Mégarbané,
Ghazi O Tadmouri, Lefkos Middleton, Giovanni Romeo, Mary-Claire King & Ephrat Levy-Lahad
the US government has proposed the development of scientific centers of excellence to solve global challenges.
We propose such a center of excellence devoted to the genomic analysis of mediterranean populations of all creeds.
this genomic focus is rooted in the region’s demographic history, builds on the area’s rapidly developing expertise in
human genetics, and will yield scientific discoveries of both local and global significance. the genome sequence data
of mediterranean populations will offer unique insights into human evolution and early human migration. the potent
combination of highly consanguineous populations in the mediterranean’s southern and eastern rims and regional
medical and scientific expertise could lead to the identification and characterization of many genes responsible for
human disease. Such discoveries will enable genetic knowledge to be translated into medical knowledge that will benefit
local populations and contribute substantially to the understanding of the genetic bases of human diseases worldwide.
In Cairo in June 2009, US President Obama spoke of the importance of international col-laboration for scientific and technological development1. This speech was followed by
fact-finding visits by American Science Envoys to the Middle East, North Africa, Europe, and South and Southeast Asia2.
Shared genes and shared cultures are key factors that unite people. As a group of Mediterranean geneticists committed to addressing local genetic issues and to borderless global scientific collaboration3, we welcome the
US initiative. We propose that human genomics is an excellent common resource for addressing common challenges and for deepening existing scientific relationships in the Mediterranean basin across all countries and populations.
In this commentary, following discussions held during the Mediterranean Medical Genetics
Meeting (MediMedGen) at Bilkent University in Ankara in June 2009, we propose a genom-ics initiative consisting of collaborative studies in human genomics that can provide a solid foundation to the American Science Envoys Program, with practical benefit to people in the region and worldwide.
A vision for Mediterranean collaboration in human genomics
Sequencing the human genome generated a landmark scientific resource that provides a common platform for biomedical research. To realize the promise of genomic medi-cine will require further advances on several fronts, including reductions in sequencing and data analysis costs to enable many more individual sequences to be generated, more complete annotation of the human genome
Tayfun Özçelik is at the Department of Molecular Biology and Genetics, Faculty of Science & Institute of Materials Science and Nanotechnology (UNAM), Bilkent University, Ankara, Turkey. Moien Kanaan is at the Department of Life Sciences, Bethlehem University, Bethlehem, Palestine. Karen B. Avraham is at the Department of Human Molecular Genetics and Biochemistry, Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, Israel. Drakoulis Yannoukakos is at the Molecular Diagnostics Laboratory, IRRP, National Centre for Scientific Research ‘Demokritos’, Aghia Paraskevi, Athens, Greece. André Mégarbané is at the Unité de Génétique Médicale, and the INSERM, Laboratoire International Associé à l’UMR_S 910, Faculté de Médecine, Université Saint-Joseph, Beirut, Lebanon. Ghazi O. Tadmouri is at the Centre for Arab Genomic Studies, Dubai, United Arab Emirates. Lefkos Middleton is at the School of Public Health, Imperial College, London, UK. Giovanni Romeo, President of the European Genetics Foundation, is at the Unità di Genetica Medica, Policlinico Universitario S. Orsola-Malpighi, Bologna, Italy. Mary-Claire King is at the Department of Genome Sciences, University of Washington School of Medicine, Seattle, Washington, USA. Ephrat Levy-Lahad is at the Medical Genetics Institute, Shaare Zedek Medical Center, Jerusalem, Israel. Correspondence to T.Ö. (tozcelik@bilkent.edu.tr) or E.L.-L. (lahad@szmc.org.il).
sequence, the creation of additional compu-tational tools and databases, the translation of human genomic research into clinical prac-tice, the delivery of services through national health systems, the development and training of a skilled workforce, and consideration of the ethical, social and legal issues that accom-pany these innovations4.
Although local issues exist, these challenges are global. The human genomics initiative for the Mediterranean region that is proposed here makes a unique contribution to science and medicine because it takes advantage of the specific strengths and characteristics of the region’s population and undertakes an inte-grated approach, using both whole-genome sequencing of Mediterranean individuals and family-based studies to identify genes for spe-cific diseases.
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Whole genome sequencing in Mediterranean individuals
Whole genome sequencing of individuals from the Mediterranean basin has not yet been performed, even though the region was one of the first stations of human migration out of Africa. Indeed, Mediterranean individuals have exerted both genetic and cultural influ-ence well beyond their ancestral home. The complete genome sequences reported so far have been for individuals of ancestries from Northwest Europe, China, Korea and sub-Saharan Africa. Although the international 1,000 Genomes Project will create a more detailed picture of human genetic variation (http://www.1000genomes.org/page.php), whole-genome sequencing of individuals from Mediterranean populations will reveal new information on human evolution, migra-tion and diversity.
Sequencing a sufficient number of rep-resentative Mediterranean individuals will provide a reference and scaffold for fur-ther genetic studies in the region. As rapid advances in DNA sequencing technology have led to marked reductions in cost as well as profound improvements in efficiency over the last decade, there are now many sequenc-ing centers worldwide, includsequenc-ing in the Mediterranean basin. This capacity could be further developed and exploited to contribute to the understanding of human genetic varia-tion in a concerted fashion. It would be feasible to generate a comprehensive Mediterranean catalog of single nucleotide and small inser-tion-deletion polymorphisms and copy num-ber variations, with corresponding allele and haplotype frequencies and linkage disequilib-rium patterns. Performing such studies locally will lead the regional community into the next stage of genomic studies. To ensure free and open access to the data generated, a virtual database, Genotheca Mediterranea, could be established.
It has become increasingly difficult to define mutations as causative as the extent of human variation has been revealed. There is a renewed realization that one means of addressing this complexity is by linking func-tional mutations with specific phenotypes, a link that is highlighted, often in stark relief, by recessive diseases. Although in most pop-ulations recessive deleterious mutations will never be fully expressed, such mutations and their effects become clearly evident in con-sanguineous populations, where individuals homozygous for a deleterious trait are
signifi-Consanguinity and disease gene identification in Mediterranean populations
The southern and eastern rims of the Mediterranean basin have among the high-est levels of consanguinity in the world, comprising part of a region of consanguin-ity that extends from the southern shores of the Mediterranean Sea through the Middle East, Mesopotamia, the Gulf and the Indian subcontinent to Southeast Asia. The roots of consanguinity in Mediterranean populations date to ancient times5, reflecting both historical
and contemporary social preferences for mar-riages between relatives. The social and cultural advantages of this practice include mainte-nance of family structure and property, and financial advantages relating to dowry. Better relations with in-laws, and the perception that consanguineous marriages might be more stable than marriages between non-relatives, are also important. At present, in many areas of the region ~25% of marriages are between first cousins. True rates of consanguinity are even higher because there is additional endogamy (that is, marriage within the extended clan; hamuleh in Arabic, hısım in Turkish)6,
lead-ing to homozygosity rates greater than those predicted by the degree of kinship alone7. By
contrast, consanguinity on the northern rim of the Mediterranean basin is generally low.
Consanguinity has a direct impact on the frequency of recessive diseases. With multiple layers of consanguinity, the number of indi-viduals affected with any recessive disease is proportional to the disease allele frequency. By contrast, in a large, randomly mating pop-ulation, the number of affected individuals is proportional to the square of the disease allele frequency8. Coupled with the large family size
that is characteristic of the southern rim of the Mediterranean and the Middle East, this statis-tic results in increased frequency of recessive disease, creating human and medical chal-lenges, but also the scientific opportunities to address them.
Recessive diseases in consanguineous com-munities vary in frequency, based on the ages of the mutations responsible for them and selec-tive pressures on the phenotype9. The
hemo-globinopathies, G6PD deficiency and familial Mediterranean fever are frequent throughout the region. Inherited hearing loss, Bardet-Biedl syndrome and Meckel Gruber syndrome are frequent in many communities in the region. Other conditions appear in a local community or clan, or specifically in one family. The
num-been studied. For example, of the 577 reces-sive diseases that have been reported in Arab families (http://www.cags.org.ae/ctga_search. html), the responsible loci are not known for 168. Many other recessive diseases, especially those confined to single families, are not even reported.
The gap in identifying genes responsi-ble for Mendelian diseases is not unique to Mediterranean populations: the molecular bases of at least 3,800 known or suspected Mendelian diseases are unknown (http://www.ncbi.nlm. nih.gov/sites/entrez?db=omim). Southern and eastern Mediterranean populations are unique in that for recessive traits in consanguineous communities, identification of the causative genes is eminently feasible using homozygosity mapping and sequencing. The success of this approach can be seen from the large number of disease genes that have been identified by study-ing Mediterranean families (Table 1). Current genomics research in the Mediterranean basin
Molecular studies of disease genes began in the 1980s with the identification of the muta-tion spectrum of X-linked diseases such as Duchenne/Becker muscular dystrophy and hemophilia, and recessive diseases such as the thalassemias, phenylketonuria and cystic fibrosis. These studies extended in the 1990s to linkage mapping of rare diseases, and have evolved today to homozygosity mapping using SNP arrays, which is powerful enough to identify disease loci even in families too small to obtain meaningful results using tradi-tional linkage approaches10. In the early years
genetic analysis of Mediterranean families was often performed outside the region, in col-laborations with American and European cen-ters. However, over time these collaborations have evolved and genetic analyses are increas-ingly performed in regional laboratories. Examples of genes that have been identified in the region include those responsible for deaf-ness (FGF3, MYO3A, OTOA, OTOF, POU4F3, SERPINB6, TECTA, TRIOBP, WHRN), neu-rodevelopmental disorders (ALS2, FA2H, FGD4, SNAP29, VLDLR, VRK1) and other rare diseases (ALX1, BBS10, CHST14, DDR2, SLC34A2, TAC3, TACR3) (see Table 1 for a comprehensive list). In parallel, biobanks and genomic databases funded through governmental research programs have been established in several countries in the region, with active participation in Orphanet (http:// www.orpha.net/consor/cgi-bin/index.php),
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which in the near future might be limited only by the phenotype discovery rate.
World Health Organization statistics indi-cate that the global burden of disease is shifting from infectious to noncommunicable diseases11.
Many of these diseases are genetically influ-enced. The responsible genes can be identified using population resources and tools now at hand. A concentrated effort to solve the genetic bases of noncommunicable diseases will have an important public health impact far beyond the specific alleles identified in the first families to be studied. The genetic dissection of well char-acterized disease phenotypes in large kindreds will reveal genes that underlie complex, hetero-geneous diseases. Indeed, pathways relevant to common diseases are often identified through genes responsible for related rare disorders12. Translating human genomic research into clinical practice
As a consequence of consanguinity, the preva-lence at birth of severe congenital genetic disor-ders in the eastern Mediterranean is among the highest in the world: >65 affected children per 1,000 live births13. From a regional perspective,
programs that address recessive diseases have a high priority and need to go beyond gene identi-fication to the characterization of the mutational spectrum relevant to each locale, and to the pro-vision of community-based medical genetics services. This extremely sensitive issue, owing to its ethical, legal and social aspects, can best be addressed by professionals from the same cul-tures as the affected families, and this is most likely to lead to clinically effective outcomes. From a global perspective, this agenda is rele-vant to the challenges of the post-genome era14,
especially in the fields of personalized medicine and identification of new drug targets emerg-ing from genomic analysis of common and rare diseases. According to currently available statistics, more than 1,500 laboratories perform genetic tests in the EU, and the annual growth in testing is close to 300%. With a population size comparable to the EU, the development, harmonization, validation and standardization of genetic testing services is a high-priority area in the Mediterranean basin.
The implementation and delivery of services through national health systems is not easy, but the large and diverse populations of the Mediterranean basin have access to excellent universities, institutes and clinics. In many parts of the region, medical genetics is a recognized clinical specialty or sub-specialty, strengthened by highly trained dysmorphologists, pediatri-cians and human geneticists. Close collaboration with the European Society of Human Genetics, the American Society of Human Genetics and the American College of Medical Genetics has
led to many national and regional congresses, workshops, and symposia focused on training, education, and workforce planning in medi-cal genetics. Future MediMedGen meetings are planned, including one in Cyprus in 2011. The Mediterranean basin is also the home of the European Genetics Foundation, which organizes regular courses in genetic medicine, attended by more than 6,000 students over the last two decades (http://www.eurogene.eu/). To address the standardization and harmo-nization of genetics services, Mediterranean geneticists have taken active roles in projects such as EuroGenTest (http://www.eurogentest. org/), MedGenMed and MedGeNet (http:// www.eurogene.eu/), through which resources for assessing and addressing ethical, social and legal issues are also available (http://www.cags. org.ae/ctga_search.html). Finally, progress in the computational use of medical and genomic data is reflected in genetic and genomic data-bases of Mediterranean populations that have already been launched15. We predict that these
assets will be crucial for the integration of genet-ics research into the delivery of health outcomes in the region and the world.
A plan for the future
On the basis of these considerations, we pro-pose an international collaborative Center of Excellence for Genomics Research in the Mediterranean region, supported by inter-national and inter-national funding agencies. We suggest that this Center of Excellence be geo-graphically decentralized and function as a network of researchers and genomics research centers whose primary remit would be to sup-port and facilitate joint research proposals. Members of the Center would include sci-entists from the region and those supporting the development of genomics in the region. They would engage in projects centered in Mediterranean laboratories whenever pos-sible, and involving transfer of technology and training, to make the Mediterranean focus increasingly realistic with time.
There is much greater strength in using resources to support science in existing insti-tutions rather than creating a new physical structure. A decentralized, international, col-laborative, investigator-initiated model alle-viates hurdles of bureaucracy and facilitates international decision-making. We believe that work to facilitate the generation of whole-genome sequence data from representative Mediterranean populations, and the discovery and characterization of genes based on well defined phenotypes in large kindreds and/or consanguineous families, should be scientifi-cally and socially attractive to funding agen-cies within and beyond the Mediterranean
region. A wide range of human traits, both rare and common, could be evaluated. The proposed scientific structure and objectives are excellent models and realistic goals for collaborative genomics for human health and cooperation in the Mediterranean basin, and could have an important impact on public health.
Conclusion
During the past two decades, working with families from the Mediterranean region, sci-entists from Algeria, Cyprus, Egypt, France, Greece, Israel, Italy, Jordan, Lebanon, Morocco, Palestine, Tunisia and Turkey have collaborated with each other and with geneticists worldwide to identify the genes responsible for many inher-ited diseases, both common and rare. Active collaborations across the region are presently exploring human genomic variation to bet-ter understand susceptibility and resistance to disease. These projects demonstrate the shared culture and goals of human genetics, and serve as a testimony to the commitment to interna-tional collaboration. The present interest of the US government encourages us to take another important step in these efforts.
ACKNOWLEDGMENTS
This Commentary is dedicated to the memory of Ihsan Dogramaci, a pioneer and reformer in child health and higher education, one of the founders of WHO, the longest serving Executive Board member of UNICEF and a tireless campaigner for world peace.
COMPETING FINANCIAL INTERESTS
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G en et . 38 , 1 1 8 4 –1 1 9 1 ( 2 0 0 6 ) ta l c on tr ac tu re s yn dr om e 2 6 0 7 5 9 8 ER B B 3 Is ra el ( B ed ou in ) Am . J . H um . G en et . 81 , 5 8 9 –5 9 5 ( 2 0 0 7 ) ta l c on tr ac tu ra l s yn dr om e 3 6 1 1 3 6 9 PI P5 K 1C Is ra el ( B ed ou in ) Am . J . H um . G en et . 81 , 5 3 0 –5 3 9 ( 2 0 0 7 ) (c on ti nu ed ) m pl es o f ge ne s fo r m en de lia n di se as es id en ti fi ed in c on sa ng ui ne ou s fa m ili es f ro m t he m ed it er ra ne an r eg io n (c on ti nu ed ) m M en de lia n In he ri ta nc e in M an O M IM # G en e Fa m ily o ri gi n R ef er en ce , d ys m ye lin at in g an d sp as ti c pa ra pa re si s w it h or w it ho ut d ys to ni a 6 1 2 4 4 3 FA 2H Is ra el ( P al es ti ni an ) Am . J . H um . G en et . 83 , 6 4 3 –6 4 8 ( 2 0 0 8 ) c on ge ni ta l g en er al iz ed , t yp e 2 2 6 9 7 0 0 B SC L2 Le ba no n, T ur ke y N at . G en et . 28 , 3 6 5 –3 7 0 ( 2 0 0 1 ) cu te in fa nt ile 6 1 3 0 7 0 TR M U Is ra el ( Ye m en it e Je w is h) Am . J . H um . G en et . 85 , 4 0 1 –4 0 7 ( 2 0 0 9 ) a lo pe ci a, c ut is la xa a nd s co lio si s 6 1 3 0 7 5 R IN 2 Is ra el ( P al es ti ni an ) Am . J . H um . G en et . 85 , 2 5 4 –2 6 3 ( 2 0 0 9 ) m e 6 0 9 6 2 8 LP IN 2 Jo rd an J. M ed . G en et . 42 , 5 5 1 –5 5 7 ( 2 0 0 5 ) 2 4 8 3 0 0 SL U R P1 A lg er ia , C ro at ia H um . M ol . G en et . 10 , 8 7 5 –8 8 0 ( 2 0 0 1 ) o st eo dy sp la st ic p ri m or di al d w ar fi sm , t yp e II 2 1 0 7 2 0 PC N T2 Le ba no n Sc ie nc e 319 , 8 1 6 –8 1 9 ( 2 0 0 8 ) s ei zu re s an d de ve lo pm en ta l d el ay 6 1 3 4 0 2 PN K P It al y, P al es ti ne , J or da n, T ur ke y N at . G en et . 42 , 2 4 5 –2 4 9 ( 2 0 1 0 ) c om pl ex I V de fi ci en cy 2 2 0 1 1 0 FA ST K D 2 Is ra el ( B ed ou in ) Am . J . H um . G en et . 83 , 4 1 5 –4 2 3 ( 2 0 0 8 ) D N A d ep le ti on s yn dr om e, e ne ph al om yo pa th ic f or m w it h m et hy lm al on ic om al r ec es si ve 6 1 2 0 7 3 SU CL A2 Is ra el ( P al es ti ni an ) Am . J . H um . G en et . 76 , 1 0 8 1 –1 0 8 6 ( 2 0 0 5 ) D N A d ep le ti on s yn dr om e, h ep at oc er eb ra l f or m , a ut os om al r ec es si ve 2 5 1 8 8 0 D G U O K Is ra el ( D ru ze ) N at . G en et . 29 , 3 3 7 –3 4 1 ( 2 0 0 1 ) I V 2 5 2 6 5 0 M CO LN 1 Is ra el ( A sh ke na zi J ew is h) N at . G en et . 26 , 1 1 8 –1 2 1 ( 2 0 0 0 ) iu m s yn dr om e, E sc ob ar v ar ia nt 2 6 5 0 0 0 CH R N G Le ba no n, T ur ke y Am . J . H um . G en et . 79 , 3 0 3 –3 1 2 ( 2 0 0 6 ) , a cu te r ec ur re nt , a ut os om al r ec es si ve 2 6 8 2 0 0 LP IN 1 Is ra el ( P al es ti ni an ) Am . J . H um . G en et . 83 , 4 8 9 –4 9 4 ( 2 0 0 8 ) ti on w it h br ai n ir on a cc um ul at io n 2 A 2 5 6 6 0 0 PL A2 G 6 Is ra el ( B ed ou in ) Am . J . H um . G en et . 79, 9 4 2 –9 4 8 ( 2 0 0 6 ) er m al d ys pl as ia 2 5 7 9 8 0 W N T1 0A Le ba no n Am . J . H um . G en et . 81 , 8 2 1 –8 2 8 ( 2 0 0 7 ) pe rf ec ta N A FK B P6 5 Tu rk ey Am . J . H um . G en et . 86 , 5 5 1 –5 5 9 ( 2 0 1 0 ) re s yn dr om e 2 4 5 0 0 0 CT SC E gy pt , L eb an on N at . G en et . 23 , 4 2 1 –4 2 4 ( 1 9 9 9 ) in a 2 6 0 9 5 9 7 AL X4 Tu rk ey H um . M ol . G en et . 18 , 4 3 5 7 –4 3 6 6 ( 2 0 0 9 ) gg re ss iv e, 1 1 7 0 6 5 0 CT SC Jo rd an , T ur ke y J. M ed . G en et . 37 , 9 5 –1 0 1 ( 2 0 0 0 ) em br an ou s os te od ys pl as ia w it h sc le ro si ng le uk oe nc ep ha lo pa th y 2 2 1 7 7 0 TR EM 2 Le ba no n H um . M ut at . 29 , E 1 9 4 –E 2 0 4 ( 2 0 0 8 ) b ila te ra l f ro nt op ar ie ta l 6 0 6 8 5 4 G PR 56 Is ra el ( P al es ti ni an ) Sc ie nc e 303 , 2 0 3 3 –2 0 3 6 ( 2 0 0 4 ) r hy po pl as ia t yp e 1 6 0 7 5 9 6 VR K 1 Is ra el ( A sh ke na zi J ew is h) Am . J . H um . G en et . 85 , 2 8 1 –2 8 9 ( 2 0 0 9 ) r hy po pl as ia t yp e 6 6 1 1 5 2 3 R AR S2 Is ra el ( S ep ha rd ic J ew is h) Am . J . H um . G en et . 81 , 8 5 7 –8 6 2 ( 2 0 0 7 ) ol ar m ic ro lit hi as is 2 6 5 1 0 0 SL C3 4A 2 Tu rk ey Am . J . H um . G en et . 79 , 6 5 0 –6 5 6 ( 2 0 0 6 ) de rm at it is w it h ps or ia si fo rm e le m en ts 6 1 0 2 2 7 ZN F7 50 Is ra el ( M or oc ca n Je w is h) N at . G en et . 38 , 7 4 9 –7 5 1 ( 2 0 0 6 ) m al e, w it h dy sg en es is o f ki dn ey s, a dr en al s an d lu ng s 6 1 1 8 1 2 W N T4 Is ra el ( P al es ti ni an ) Am . J . H um . G en et . 82 , 3 9 –4 7 ( 2 0 0 8 ) m al fo rm at io n 6 2 2 5 3 0 0 W N T1 0B Tu rk ey H um . M ol . G en et . 17 , 2 6 4 4 –2 6 5 3 ( 2 0 0 8 ) a-ep ip hy se al d ys pl as ia , s ho rt li m b-ha nd t yp e 2 7 1 6 6 5 D D R 2 Is ra el ( S ep ha rd ic J ew is h) , P al es ti ne Am . J . H um . G en et . 84 , 8 0 –8 4 ( 2 0 0 9 ) om e 1 2 7 3 7 5 0 CU L7 Fr an ce , I ta ly , L eb an on , P or tu ga l N at . G en et . 37 , 1 1 1 9 –1 1 2 4 ( 2 0 0 5 ) si s, h yp er ph os ph at em ic f am ili al 2 1 1 9 0 0 G AL N T3 Is ra el ( D ru ze ), P al es ti ne N at . G en et . 36 , 5 7 9 –5 8 1 ( 2 0 0 4 ) si s, n or m op ho sp ha te m ic f am ili al 6 1 0 4 5 5 SA M D 9 Is ra el ( Ye m en it e Je w is h) Am . J . H um . G en et . 79 , 7 5 9 –7 6 4 ( 2 0 0 6 ) e, t yp e IG 6 0 6 9 4 3 U SH 1G Jo rd an ( P al es ti ni an ) H um . G en et . 110 , 3 4 8 –3 5 0 ( 2 0 0 2 ) ili al is ol at ed d ef ic ie nc y of 2 7 7 4 6 0 TT PA Fr an ce , I ta ly , M or oc co , T un is ia N at . G en et . 9, 1 4 1 –1 4 5 ( 1 9 9 5 ) s yn dr om e 6 0 0 1 1 8 R AB 3G AP Le ba no n, M or oc co N at . G en et . 37 , 2 2 1 –2 2 3 ( 2 0 0 5 ) an i s yn dr om e, a ut os om al r ec es si ve 2 7 7 6 0 0 AD AM TS 10 Le ba no n Am . J . H um . G en et . 75 , 8 0 1 –8 0 6 ( 2 0 0 4 ) om e 2 6 0 4 9 2 8 CI SD 2 Jo rd an Am . J . H um . G en et . 81 , 6 7 3 –6 8 3 ( 2 0 0 7 )
© 20 10 Nat ur e Amer ica, Inc. All r ights r eser ved. Table 1 e xa m pl es o f ge ne s fo r m en de lia n di se as es id en ti fi ed in c on sa ng ui ne ou s fa m ili es f ro m t he m ed it er ra ne an r eg io n D is ea se I D f ro m M en de lia n In he ri ta nc e in M an O M IM # G en e Fa m ily o ri gi n R ef er en ce A dd uc te d th um b-cl ub fo ot s yn dr om e 6 0 1 7 7 6 CH ST 14 Tu rk ey Am . J . H um . G en et . 85 , 8 7 3 –8 8 2 ( 2 0 0 9 ) A lo pe ci a, n eu ro lo gi c de fe ct s an d en do cr in op at hy 6 1 2 0 7 9 R B M 28 Is ra el ( P al es ti ni an ) Am . J . H um . G en et . 82 , 1 1 1 4 –1 1 2 1 ( 2 0 0 8 ) A m yo tr op hi c la te ra l s cl er os is 2 , j uv en ile 2 0 5 1 0 0 AL S2 Tu ni si a N at . G en et . 29 , 1 6 0 –1 6 5 ( 2 0 0 1 ) A ta xi a-te la ng ie ct as ia 2 0 8 9 0 0 AT M Is ra el ( M or oc ca n Je w is h) Sc ie nc e 268 , 1 7 4 9 –1 7 5 3 ( 1 9 9 5 ) B ar de t-B ie dl s yn dr om e 1 0 2 0 9 9 0 0 B B S1 0 Le ba no n, T ur ke y N at . G en et . 38 , 5 2 1 –5 2 4 ( 2 0 0 6 ) B ir k-B ar el m en ta l r et ar da ti on d ys m or ph is m s yn dr om e 6 1 2 2 9 2 K CN K 9 Is ra el ( P al es ti ni an ) Am . J . H um . G en et . 83 , 1 9 3 –1 9 9 ( 2 0 0 8 ) C en an i s yn da ct yl is m 2 1 2 7 8 0 LR P4 E gy pt , T ur ke y Am . J . H um . G en et . 86 , 1 –1 1 ( 2 0 1 0 ) C er eb el la r at ax ia , m en ta l r et ar da ti on a nd d is eq ui lib ri um s yn dr om e 1 2 2 4 0 5 0 VL D LR Tu rk ey Pr oc . N at l. Ac ad . S ci . U SA 105 , 4 2 3 2 –4 2 3 6 ( 2 0 0 8 ) C er eb ra l d ys ge ne si s, n eu ro pa th y, ic ht hy os is a nd p al m op la nt ar k er at od er m a sy nd ro m e 6 0 9 5 2 8 SN AP 29 Is ra el ( P al es ti ni an ) Am . J . H um . G en et . 77 , 2 4 2 –2 5 1 ( 2 0 0 5 ) C ha rc ot -M ar ie -T oo th d is ea se , t yp e 4 H 6 0 9 3 1 1 FG D 4 A lg er ia , L eb an on Am . J . H um . G en et . 81 , 1 –1 6 ( 2 0 0 7 ) C ha rc ot -M ar ie -T oo th d is ea se , t yp e 4 A 2 1 4 4 0 0 G D AP 1 Tu ni si a N at . G en et . 30 , 2 1 –2 2 ( 2 0 0 2 ) C ut is L ax a, a ut os om al r ec es si ve , t yp e II B 6 1 2 9 4 0 PY CR 1 It al y, J or da n, P al es ti ne , T ur ke y N at . G en et . 41 , 1 0 1 6 –1 0 2 1 ( 2 0 0 9 ) D yg gv e-M el ch io r-C la us en d is ea se 2 2 3 8 0 0 D YM Le ba no n, P or tu ga l, M or oc co , T un is ia J. M ed . G en et . 39 , 7 1 4 –7 1 7 ( 2 0 0 2 ) D ea fn es s, c on ge ni ta l w it h in ne r ea r ag en es is , m ic ro ti a an d m ic ro do nt ia 6 1 0 7 0 6 FG F3 Tu rk ey Am . J . H um . G en et . 80 , 3 3 8 –3 4 4 ( 2 0 0 7 ) D ea fn es s, a ut os om al r ec es si ve 9 , D FN B 9 6 0 1 0 7 1 O TO F Le ba no n N at . G en et . 21 , 3 6 3 –3 6 9 ( 1 9 9 9 ) D ea fn es s, a ut os om al d om in an t 1 5 , D FN A 1 5 6 0 2 4 5 9 PO U 4F 3 Is ra el ( It al ia n Je w is h) Sc ie nc e 279 , 1 9 5 0 –1 9 5 4 ( 1 9 9 8 ) D ea fn es s, a ut os om al r ec es si ve 2 1 , D FN B 2 1 6 0 3 6 2 9 TE CT A Le ba no n H um . M ol . G en et . 8, 4 0 9 –4 1 2 ( 1 9 9 9 ) D ea fn es s, a ut os om al r ec es si ve 2 2 , D FN B 2 2 6 0 7 0 3 9 O TO A P al es ti ne Pr oc . N at l. Ac ad . S ci . U SA 99 , 6 2 4 0 –6 2 4 5 ( 2 0 0 2 ) D ea fn es s, a ut os om al r ec es si ve 2 8 , D FN B 2 8 6 0 9 8 2 3 TR IO B P P al es ti ne Am . J . H um . G en et . 78 , 1 4 4 –1 5 2 ( 2 0 0 6 ) D ea fn es s, a ut os om al r ec es si ve 3 0 , D FN B 3 0 6 0 7 1 0 1 M YO 3A Is ra el ( Ir aq i J ew is h) Pr oc . N at l. Ac ad . S ci . U SA 99 , 7 5 1 8 –7 5 2 3 ( 2 0 0 2 ) D ea fn es s, a ut os om al r ec es si ve 3 1 , D FN B 3 1 6 0 7 0 8 4 W H R N P al es ti ne Eu r. J. H um . G en et . 10 , 2 1 0 –2 1 2 ( 2 0 0 2 ) D ea fn es s, a ut os om al r ec es iv e 9 1 , D FN B 9 1 N A SE R PI N B 6 Tu rk ey Am . J . H um . G en et . 86 , 7 9 7 –8 0 4 ( 2 0 1 0 ) H yp er tr op hi c ne ur op at hy o f D ej er in e-S ot ta s 1 4 5 9 0 0 PR X Le ba no n H um . M ol . G en et . 10 , 4 1 5 –4 2 1 ( 2 0 0 1 ) E ct op ia le nt is , i so la te d, a ut os om al r ec es si ve 2 2 5 1 0 0 AD AM TS L4 Ir aq , J or da n Am . J . H um . G en et . 84 , 2 7 4 –2 7 8 ( 2 0 0 9 ) E pi le ps y, p ro gr es si ve m yo cl on ic , 1 B 6 1 2 4 3 7 PR IC K LE 1 Is ra el ( P al es ti ni an ), J or da n Am . J . H um . G en et . 83 , 5 7 2 –5 8 1 ( 2 0 0 8 ) E xo cr in e pa nc re at ic in su ff ic ie nc y, d ys er yt hr op oe it ic a ne m ia a nd c al va ri al h yp er os to si s 6 1 2 7 1 4 CO X4 I2 Is ra el ( P al es ti ni an ) Am . J . H um . G en et . 84 , 4 1 2 –4 1 7 ( 2 0 0 9 ) Fr an k-Te r H aa r sy nd ro m e 2 4 9 4 2 0 SH 3P XD 2B Is ra el , L eb an on , T ur ke y Am . J . H um . G en et . 86 , 2 5 4 –2 6 1 ( 2 0 1 0 ) Fr as er s yn dr om e 2 1 9 0 0 0 FR AS 1 Fr an ce , G re ec e, L eb an on , S pa in N at . G en et . 34 , 2 0 3 –2 0 8 ( 2 0 0 3 ) Fr on to na sa l d ys pl as ia N A AL X1 Tu rk ey Am . J . H um . G en et . 86 , 7 8 9 –7 9 6 ( 2 0 1 0 ) H s yn dr om e 6 1 2 3 9 1 SL C2 9A 3 Is ra el ( P al es ti ni an ), B ul ga ri a Am . J . H um . G en et . 83 , 5 2 9 –5 3 4 ( 2 0 0 8 ) H yp er os to si s-hy pe rp ho sp ha te m ia s yn dr om e 6 1 0 2 3 3 G AL N T3 Is ra el ( D ru ze ), P al es ti ne J. M ol . M ed . 83 , 3 3 –3 8 ( 2 0 0 5 ) H yp og on ad ot ro pi c hy po go na di sm 1 4 6 1 1 0 TA C3 , T AC R 3 Tu rk ey N at . G en et . 41 , 3 5 4 –3 5 8 ( 2 0 0 9 ) H yp ot ri ch os is , c on ge ni ta l, w it h ju ve ni le m ac ul ar d ys tr op hy 6 0 1 5 5 3 CD H 3 Is ra el ( D ru ze ) N at . G en et . 29 , 1 3 4 –1 3 6 ( 2 0 0 1 ) Ic ht hy os is , l am el la r 3 6 0 4 7 7 7 CY P4 F2 2 A lg er ia , F ra nc e, I ta ly , L eb an on H um . M ol . G en et . 15 , 7 6 7 –7 7 6 ( 2 0 0 6 ) Ic ht hy os is w it h hy po tr ic ho si s, a ut os om al r ec es si ve 6 1 0 7 6 5 ST 14 Is ra el ( P al es ti ni an ) Am . J . H um . G en et . 80 , 4 6 7 –4 7 7 ( 2 0 0 7 ) Ja lil i s yn dr om e 2 1 7 0 8 0 CN N M 4 K os ov o, L eb an on Am . J . H um . G en et . 84 , 2 5 9 –2 6 5 ( 2 0 0 9 ) Jo ub er t sy nd ro m e 2 6 0 8 0 9 1 TM EM 21 6 Is ra el ( A sh ke na zi J ew is h) Am . J . H um . G en et . 86 , 9 3 –9 7 ( 2 0 1 0 ) K in dl er s yn dr om e 1 7 3 6 5 0 FE R M T1 A lg er ia , T un is ia H um . M ol . G en et . 12 , 9 2 5 –9 3 5 ( 2 0 0 3 ) K ra bb e di se as e 2 4 5 2 0 0 G AL C Is ra el ( P al es ti ni an ) Am . J . H um G en et . 53 , 1 2 5 0 –1 2 5 5 ( 1 9 9 3 ) K uf or -R ak eb s yn dr om e 6 0 6 6 9 3 AT P1 3A 2 Jo rd an N at . G en et . 38 , 1 1 8 4 –1 1 9 1 ( 2 0 0 6 ) Le th al c on ge ni ta l c on tr ac tu re s yn dr om e 2 6 0 7 5 9 8 ER B B 3 Is ra el ( B ed ou in ) Am . J . H um . G en et . 81 , 5 8 9 –5 9 5 ( 2 0 0 7 ) Le th al c on ge ni ta l c on tr ac tu ra l s yn dr om e 3 6 1 1 3 6 9 PI P5 K 1C Is ra el ( B ed ou in ) Am . J . H um . G en et . 81 , 5 3 0 –5 3 9 ( 2 0 0 7 ) (c on ti nu ed ) Table 1 e xa m pl es o f ge ne s fo r m en de lia n di se as es id en ti fi ed in c on sa ng ui ne ou s fa m ili es f ro m t he m ed it er ra ne an r eg io n (c on ti nu ed ) D is ea se I D f ro m M en de lia n In he ri ta nc e in M an O M IM # G en e Fa m ily o ri gi n R ef er en ce Le uk od ys tr op hy , d ys m ye lin at in g an d sp as ti c pa ra pa re si s w it h or w it ho ut d ys to ni a 6 1 2 4 4 3 FA 2H Is ra el ( P al es ti ni an ) Am . J . H um . G en et . 83 , 6 4 3 –6 4 8 ( 2 0 0 8 ) Li po dy st ro ph y, c on ge ni ta l g en er al iz ed , t yp e 2 2 6 9 7 0 0 B SC L2 Le ba no n, T ur ke y N at . G en et . 28 , 3 6 5 –3 7 0 ( 2 0 0 1 ) Li ve r fa ilu re , a cu te in fa nt ile 6 1 3 0 7 0 TR M U Is ra el ( Ye m en it e Je w is h) Am . J . H um . G en et . 85 , 4 0 1 –4 0 7 ( 2 0 0 9 ) M ac ro ce ph al y, a lo pe ci a, c ut is la xa a nd s co lio si s 6 1 3 0 7 5 R IN 2 Is ra el ( P al es ti ni an ) Am . J . H um . G en et . 85 , 2 5 4 –2 6 3 ( 2 0 0 9 ) M aj ee d sy nd ro m e 6 0 9 6 2 8 LP IN 2 Jo rd an J. M ed . G en et . 42 , 5 5 1 –5 5 7 ( 2 0 0 5 ) M al d e M el ed a 2 4 8 3 0 0 SL U R P1 A lg er ia , C ro at ia H um . M ol . G en et . 10 , 8 7 5 –8 8 0 ( 2 0 0 1 ) M ic ro ce ph al ic o st eo dy sp la st ic p ri m or di al d w ar fi sm , t yp e II 2 1 0 7 2 0 PC N T2 Le ba no n Sc ie nc e 319 , 8 1 6 –8 1 9 ( 2 0 0 8 ) M ic ro ce ph al y, s ei zu re s an d de ve lo pm en ta l d el ay 6 1 3 4 0 2 PN K P It al y, P al es ti ne , J or da n, T ur ke y N at . G en et . 42 , 2 4 5 –2 4 9 ( 2 0 1 0 ) M it oc ho nd ri al c om pl ex I V de fi ci en cy 2 2 0 1 1 0 FA ST K D 2 Is ra el ( B ed ou in ) Am . J . H um . G en et . 83 , 4 1 5 –4 2 3 ( 2 0 0 8 ) M it oc ho nd ri al D N A d ep le ti on s yn dr om e, e ne ph al om yo pa th ic f or m w it h m et hy lm al on ic ac id ur is , a ut os om al r ec es si ve 6 1 2 0 7 3 SU CL A2 Is ra el ( P al es ti ni an ) Am . J . H um . G en et . 76 , 1 0 8 1 –1 0 8 6 ( 2 0 0 5 ) M it oc ho nd ri al D N A d ep le ti on s yn dr om e, h ep at oc er eb ra l f or m , a ut os om al r ec es si ve 2 5 1 8 8 0 D G U O K Is ra el ( D ru ze ) N at . G en et . 29 , 3 3 7 –3 4 1 ( 2 0 0 1 ) M uc ol ip id os is I V 2 5 2 6 5 0 M CO LN 1 Is ra el ( A sh ke na zi J ew is h) N at . G en et . 26 , 1 1 8 –1 2 1 ( 2 0 0 0 ) M ul ti pl e pt er yg iu m s yn dr om e, E sc ob ar v ar ia nt 2 6 5 0 0 0 CH R N G Le ba no n, T ur ke y Am . J . H um . G en et . 79 , 3 0 3 –3 1 2 ( 2 0 0 6 ) M yo gl ob in ur ia , a cu te r ec ur re nt , a ut os om al r ec es si ve 2 6 8 2 0 0 LP IN 1 Is ra el ( P al es ti ni an ) Am . J . H um . G en et . 83 , 4 8 9 –4 9 4 ( 2 0 0 8 ) N eu ro de ge ne ra ti on w it h br ai n ir on a cc um ul at io n 2 A 2 5 6 6 0 0 PL A2 G 6 Is ra el ( B ed ou in ) Am . J . H um . G en et . 79, 9 4 2 –9 4 8 ( 2 0 0 6 ) O do nt oo ny ch od er m al d ys pl as ia 2 5 7 9 8 0 W N T1 0A Le ba no n Am . J . H um . G en et . 81 , 8 2 1 –8 2 8 ( 2 0 0 7 ) O st eo ge ne si s im pe rf ec ta N A FK B P6 5 Tu rk ey Am . J . H um . G en et . 86 , 5 5 1 –5 5 9 ( 2 0 1 0 ) P ap ill on -L ef ev re s yn dr om e 2 4 5 0 0 0 CT SC E gy pt , L eb an on N at . G en et . 23 , 4 2 1 –4 2 4 ( 1 9 9 9 ) P ar ie ta l f or am in a 2 6 0 9 5 9 7 AL X4 Tu rk ey H um . M ol . G en et . 18 , 4 3 5 7 –4 3 6 6 ( 2 0 0 9 ) P er io do nt it is , a gg re ss iv e, 1 1 7 0 6 5 0 CT SC Jo rd an , T ur ke y J. M ed . G en et . 37 , 9 5 –1 0 1 ( 2 0 0 0 ) P ol yc ys ti c lip om em br an ou s os te od ys pl as ia w it h sc le ro si ng le uk oe nc ep ha lo pa th y 2 2 1 7 7 0 TR EM 2 Le ba no n H um . M ut at . 29 , E 1 9 4 –E 2 0 4 ( 2 0 0 8 ) P ol ym ic ro gy ri a, b ila te ra l f ro nt op ar ie ta l 6 0 6 8 5 4 G PR 56 Is ra el ( P al es ti ni an ) Sc ie nc e 303 , 2 0 3 3 –2 0 3 6 ( 2 0 0 4 ) P on to ce re be lla r hy po pl as ia t yp e 1 6 0 7 5 9 6 VR K 1 Is ra el ( A sh ke na zi J ew is h) Am . J . H um . G en et . 85 , 2 8 1 –2 8 9 ( 2 0 0 9 ) P on to ce re be lla r hy po pl as ia t yp e 6 6 1 1 5 2 3 R AR S2 Is ra el ( S ep ha rd ic J ew is h) Am . J . H um . G en et . 81 , 8 5 7 –8 6 2 ( 2 0 0 7 ) P ul m on ar y al ve ol ar m ic ro lit hi as is 2 6 5 1 0 0 SL C3 4A 2 Tu rk ey Am . J . H um . G en et . 79 , 6 5 0 –6 5 6 ( 2 0 0 6 ) S eb or rh ea -l ik e de rm at it is w it h ps or ia si fo rm e le m en ts 6 1 0 2 2 7 ZN F7 50 Is ra el ( M or oc ca n Je w is h) N at . G en et . 38 , 7 4 9 –7 5 1 ( 2 0 0 6 ) S ex r ev er sa l, fe m al e, w it h dy sg en es is o f ki dn ey s, a dr en al s an d lu ng s 6 1 1 8 1 2 W N T4 Is ra el ( P al es ti ni an ) Am . J . H um . G en et . 82 , 3 9 –4 7 ( 2 0 0 8 ) S pl it -h an d/ fo ot m al fo rm at io n 6 2 2 5 3 0 0 W N T1 0B Tu rk ey H um . M ol . G en et . 17 , 2 6 4 4 –2 6 5 3 ( 2 0 0 8 ) S po nd yl o-m et a-ep ip hy se al d ys pl as ia , s ho rt li m b-ha nd t yp e 2 7 1 6 6 5 D D R 2 Is ra el ( S ep ha rd ic J ew is h) , P al es ti ne Am . J . H um . G en et . 84 , 8 0 –8 4 ( 2 0 0 9 ) Th re e M s yn dr om e 1 2 7 3 7 5 0 CU L7 Fr an ce , I ta ly , L eb an on , P or tu ga l N at . G en et . 37 , 1 1 1 9 –1 1 2 4 ( 2 0 0 5 ) Tu m or al c al ci no si s, h yp er ph os ph at em ic f am ili al 2 1 1 9 0 0 G AL N T3 Is ra el ( D ru ze ), P al es ti ne N at . G en et . 36 , 5 7 9 –5 8 1 ( 2 0 0 4 ) Tu m or al c al ci no si s, n or m op ho sp ha te m ic f am ili al 6 1 0 4 5 5 SA M D 9 Is ra el ( Ye m en it e Je w is h) Am . J . H um . G en et . 79 , 7 5 9 –7 6 4 ( 2 0 0 6 ) U sh er s yn dr om e, t yp e IG 6 0 6 9 4 3 U SH 1G Jo rd an ( P al es ti ni an ) H um . G en et . 110 , 3 4 8 –3 5 0 ( 2 0 0 2 ) Vi ta m in E , f am ili al is ol at ed d ef ic ie nc y of 2 7 7 4 6 0 TT PA Fr an ce , I ta ly , M or oc co , T un is ia N at . G en et . 9, 1 4 1 –1 4 5 ( 1 9 9 5 ) W ar bu rg m ic ro s yn dr om e 6 0 0 1 1 8 R AB 3G AP Le ba no n, M or oc co N at . G en et . 37 , 2 2 1 –2 2 3 ( 2 0 0 5 ) W ei ll-M ar ch es an i s yn dr om e, a ut os om al r ec es si ve 2 7 7 6 0 0 AD AM TS 10 Le ba no n Am . J . H um . G en et . 75 , 8 0 1 –8 0 6 ( 2 0 0 4 ) W ol fr am s yn dr om e 2 6 0 4 9 2 8 CI SD 2 Jo rd an Am . J . H um . G en et . 81 , 6 7 3 –6 8 3 ( 2 0 0 7 )
