chapter 1 genetic disorders in arab populations: a 2006 update · 2008. 10. 21. · genetic...

Introduction

Until recently, infectious or environmental diseases and malnutrition-related disorders constituted the major cause of ill health and mortality in Arab populations. However, progress made in healthcare standards in many Arab countries decreased the impact of such disorders in favor of an increased understanding of the molecular basis of heredity, hence, the better recognition of genetically transmitted conditions as a major cause of morbidity and mortality (Table 1.1).

Consanguinity

One of the most important factors contributing to the preponderance of genetic disorders in Arab populations is

the deep-rooted norm of consanguineous marriages (Figure 1.1). While the rates of consanguineous marriages remain unchanged or have declined in several countries, these rates have increased since the last generation in Algeria (Zaoui and Biemont, 2002), the United Arab Emirates (Al-Gazali et al., 1997), and Yemen (Jurdi and Saxena, 2003). Recently, many studies from the region have drawn strong correlations between consanguinity and hearing loss (Bener et al., 2005), infanto-youthful death rate (Hammami et al., 2005b), respiratory allergies, eczema (Bener and Janahi, 2005), congenital heart defects (Yunis et al., 2006), mental retardation, epilepsy, diabetes (Bener and Hussain, 2006), and many others (reviewed in Tadmouri, 2004a; Tadmouri et al., 2004).

Chapter 1 Genetic Disorders in Arab Populations:A 2006 Update

Ghazi Omar TadmouriCentre for Arab Genomic Studies, Dubai, United Arab Emirates

Table 1.1. Population indicators in Arab countries (2006).

G E N E T I C D I S O R D E R S I N T H E A R A B W O R L D - B A H R A I N

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The Economic Impact of Genetic Disorders

Genetic disorders are chronic in nature and often require lifelong management with no definitive cure. In the Arab World, severaldisorders, including chromosomal (Down syndrome, Turner syndrome), single-gene (sickle-cell disease, thalassemia, glucose-6-phosphate dehydrogenase deficiency, hemophilia, inborn errors ofmetabolism) and multifactorial disorders (coronary artery disease, arteriosclerosis, diabetes mellitus, hypertension, obesity) are common. Some of these disorders have assumed epidemic proportions as in the cases of sickle cell disease, alpha-thalassemia, hypertension, and diabetes mellitus. The impact of each of these disorders differs according to their severity, many of which have medical, surgical, or cosmetic consequences, as well as the genetic backgrounds of affected individuals and families.

Generally, these conditions are a leading cause of spontaneous abortion, neonatal death, increased morbidity and mortality in children and adults as well. They are a significant health care and psychosocialburden for the patient, the family, the healthcare system and the community as a whole (El-Hazmi, 1999).

In terms of economic burden, patients with genetic or partly genetic disorders have longer and more frequent hospital admissions with a higher number of surgeries than other patients (Carnevale et al., 1985; McCandless et al., 2004). Additionally, the total costs paid by patients with genetic conditions are slightly more expensive (Hall et al., 1978). These patients come frequently from outside major cities and travel farther to get better treatment regimens; hence, their families end up paying the bill more often (Carnevale et al., 1985).

Figure 1.1. Percentage of consanguineous unions of total marriages in Arab countries. Adapted from: Benallegue and Kedji, 1984 (Algeria); ENAF, 1992 (Algeria); Al-Arrayed, 1999 (Bahrain); Hafez et al., 1983 (Egypt); ENPC, 1989 (Egypt); Al-Hamamy et al., 1986 (Iraq); Khoury and Massad, 1992 (Jordan); Al-Nasser et al., 1989 (Kuwait); Al-Awadi et al., 1985 (Kuwait); Klat and Khudr, 1986 (Lebanon); Broadhead and Sehgal, 1981 (Libya); National Statistical Office, 1992 (Mauritania); Hammami et al., 2005a (Mauritania); Azelmat et al.,1987 (Morocco); Azelmat et al., 1992 (Morocco); Rajab and Patton, 2000 (Oman); Jaber et al., 1992 (Palestine); Ministry of Health, 1999 (Qatar); Bener and Alali, 2006 (Qatar); Wong and Anokute, 1990 (Saudi Arabia); El-Hazmi et al., 1995 (Saudi Arabia); Saha et al., 1990 (Sudan); Prothro and Diab, 1974 (Syria); Aloui et al., 1988 (Tunisia); Kerkeni et al., 2006 (Tunisia); Fahmy et al., 1993 (UAE); Al-Gazali et al., 1995 (UAE); Jurdi and Saxena, 2003 (Yemen); Gunaid et al., 2004 (Yemen).

G E N E T I C D I S O R D E R S I N T H E A R A B W O R L D - B A H R A I NG e n e t i c D i s o r d e r s i n A r a b P o p u l a t i o n s : A 2 0 0 6 U p d a t e

In recent years, heath economists have made significant advances in calculatingthe costs of genetic disorders and disabilities caused by various congenital abnormalities. There are now generally-accepted ‘cost of illness’ estimates for all common genetic conditions:

Beta-thalassemia: Treatment of beta-thalassemia major is currently an expen-sive option and has great financial impli-cations for any health authority where the disease has a high prevalence. The base-line results for the total lifetime treatment costs for a patient with beta-thalassemia (up to 60 years of age) are estimated to be $416,000; thus, an average of about $7000 annually (Karnon et al., 1999).

Sickle cell disease: Davis and colleagues (1997) estimated the direct cost of hospitalizations associated with sickle cell disease to be $6,300. Patients with sickle cell disease are frequent users of health care services. On average, a sickle cell disease patient is subject to one hospital admission per year and 8 outpatient visits annually. Mean total inpatient hospital charges, physician charges, and direct hospital costs per admission are estimated as $14,284 and the average length of stay varies between 4-5 days. Mean total hospital charges, physician charges, and direct hospital costs per outpatient visit are $1,162 (Nietert et al., 1999). Although most of the treatment costs are covered by governments or supported by non-governmental organizations in the region, the fact that many of the patients originate from distant areas and many could develop painful respiration usually add excessive charges and expenses that go beyond expected reimbursements.

Cystic fibrosis: Studies have shown that hospitalization costs for patients with cystic fibrosis vary according to theseverity of their disease with drug costs playing a major role in these differences.

However, economists have estimated the total costs per cystic fibrosis case to beabout $285,000 over the lifetime (Nielsen and Gyrd-Hansen, 2002) with an annual average of about $9,400 per patient of which 28% of this total cost is attributable to drug costs (Schreyogg et al., 2006).

Hemophilia: Similar to other disorders, hemophilia is a life-long disorder which creates profound physical, emotional, economic, and social problems for those afflicted. The physical disabilitiesresulting from the bleeding episodes are correlated with the degree of deficiencyof the Factor VIII protein in the blood. Accordingly, hemophiliacs would either present with a mild, moderate, or severe condition. Medical expenses vary among patients according to the severities of their conditions. In the moderate-severe group, medical expenses exceed the level of $1,000 per year (Meyers et al., 1972). Knowing that many hemophiliacs are usually denied health insurance, it is usually necessary for the parents to meet the medical costs of their hemophiliac children.

Congenital bilateral permanent childhood hearing impairment: in a recent study to estimate the economic costs of bilateral permanent childhood hearing impairment (PCHI) in the preceding year of life for children aged 7 to 9 years, the mean societal cost was estimated to be about $26,700 per child, compared with $8,000 for the normally hearing children (Schroeder et al., 2006).

In 1995, Waitzman et al. estimated the United States national total economic costs of cerebral palsy, spina bifida, trun-cus arteriosus, single ventricle, transposi-tion/double outlet right ventricle, tetral-ogy of fallot, tracheo-esophageal fistula,colorectal atresia, cleft lip or palate, atre-sia/stenosis of the small intestine, renal agenesis, urinary obstruction, lower limb


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reduction, upper limb reduction, omphalo-cele, gastroschisis, Down syndrome, and other diaphragmatic hernia as $10.8 bil-lion (2004 normalized data) for a single year’s cohort. This total cost comprises $2.8 billion in direct health care costs and $8 billion in indirect costs such as devel-opmental services, special education, and lost productivity. By comparing the total size of all Arab populations to that residing in the United States and ignoring the fact that many of these 18 birth defects occur more frequently in the region than else-where, such a cost is expected to be about $13 billion per year in all Arab countries. The share of the United Arab Emirates of this total cost would be about $130 million annually. By adding the costs related to about 2000 beta-thalassemia patients, 300 sickle cell disease patients, 200 cystic fi-brosis patients, and 50 hemophiliacs in the UAE, the total impact on the healthcare system would be estimated around $200 million per year.

Preventive Aspects of Genetic Disorders

The successful management of genetic disorders also incurs a high financial cost,which could be eased by the application of effective prevention programs in populations at risk of genetic disease (WHO, 1996). Certainly, such programs help in decreasing the impact of genetic disorders on families and societies and also lead to greater success of treatment and improve outcome and prognosis (Al-Odaib et al., 2003). A majority of Arab countries have the expertise and resources to apply most of these preventive measures, especially in the areas of newborn screening and carrier screening for prevalent genetic disorders. However, having the technology and resources alone are not enough to start effective programs. For example, population

screening should be performed only if the abnormal finding can change the clinicalmanagement, and consequently result in a favorable outcome. Such a program should be based on the economics of genetic disorders since only in the case of few disorders does the cost of screening justify the financial and emotional savingsof detecting the affected individuals. In addition, no genetic screening program may be successful if not accompanied by extensive educational activities aimed at both the general public and health care providers to grant effective participation (Khalifa, 1999). Furthermore, these programs are most successful when they are sensitive to the cultural backgrounds of populations in which they are applied (Meyer, 2005).

Methods of Data Collection for the CTGA Database

The Catalogue for Transmission Genetics in Arabs (CTGA) Database is a continu-ously updated catalogue of bibliographic material and observations on human gene variants and inherited, or heritable, ge-netic diseases in Arab individuals. Since the public release of the CTGA database in 2004, our knowledge on the presence of genetic disorders in Arab populations is continuously expanding. This process is largely driven by the different methods used at the Centre for Arab Genomic Stud-ies (CAGS) to collect data and information on genetic conditions in Arab patients. Most of the data included in the database come from the United Arab Emirates and Bahrain following two systematic reviews conducted in years 2004 and 2006, respec-tively, of all published literature on the oc-currence of genetic disorders in UAE and Bahraini nationals and Arab expatriates residing in both countries. However, data from other Arab countries are also includ-ed, though at a slower rate, mostly owing

G e n e t i c D i s o r d e r s i n A r a b P o p u l a t i o n s : A 2 0 0 6 U p d a t e

to submissions by scientists, practitioners, and researchers working in the region. It is anticipated that exhaustive systematic reviews will be conducted in other Arab countries using several alternatives meth-ods of data collection.

Bibliographic Indices: Over the last 20 years, a steady increase in the rate of international biomedical publications is recorded in almost all Arab countries (Figure 1.2). Overall, scientists affiliatedto Arab biomedical institutes produce about 2500 scientific articles annuallyaccording to the Medline bibliographic index. A similar observation is also recorded at the Index Medicus of the Eastern Mediterranean Region, which is a bibliographic index of regional health and biomedical journals. The presence of these indices has facilitated the location of articles with observations on genetic disorders in Arab patients.

In fact, international bibliographic indices, such as PubMed and SCI-Expanded, form the source of the major bulk of information collected by the CTGA database development team at the centre. They also allow almost instantaneous search for information on specific geneticdisorders in certain Arab populations using a multitude of search strategies and

syntaxes. However, careful sorting and screening of search results have to be made to avoid false-positive records especially in the case of Lebanon, Jordan, Palestine, Sudan, and Syria. For example, search for studies with addresses in Lebanon and Palestine may result with records originating from the United States and other world locations where cities with the names of Lebanon and Palestine do occur. Additionally, searching for Jordan results in many cases with false-positive answers due to the common use of the family name Jordan in many western societies. On the other hand, the terms “Sudan dye” and “Syrian hamster” are common terms that cause false-positive results while searching for data from the Arab countries Sudan and Syria.

Regional Peer-Reviewed Medical Publications: On the other hand, national peer-reviewed medical publications are also monitored at CAGS. However, most of these journals are neither indexed nor digitized. Therefore, manual search is the only method to mine information from this source. Yet, national journals are not to be underestimated as they tend to contain important information of local value with enough details not offered in many short-sized international citations. With the availability of hundreds of national

Figure 1.2. Annual biomedical publication outputs in the Arab World as indexed by Medline. Data refer to articles where the first author is affiliated to an Arab country.


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peer-reviewed medical journals, manual search is time consuming and requires the involvement of a considerable number of well-trained staff to accomplish the task of data collection and curation.

The Arab Council of CAGS as a Source of Information: A more recent source of data regarding genetic disorders in the Arab World developed soon after the formation of the Arab Council of CAGS which includes members representing 10 Arab countries: Bahrain, Egypt, Jordan, Kuwait, Lebanon, Oman, Qatar, Saudi Arabia, Sudan, and Tunisia. Through its Arab Council, the Centre for Arab Genomic Studies work with nuclear groups of leading scientists in Arab institutes to initiate local projects of data collection. Data collection either involves the random collection of information from different Arab countries or involves an aggressive search for genetic disorders in a specific country (Chapter 4) followingthe successful model implemented in the United Arab Emirates since 2004.

The CTGA Database Information Submission Form: Following the publication of a detailed description of the CTGA database in the 2006 Database Issue of the journal Nucleic Acids Research (Tadmouri et al., 2006a), the Centre for Arab Genomic Studies receives a variety of publications from scientists in the Arab World or abroad to be considered for the CTGA database on genetic disorders in Arab populations. The CTGA database development team continuously updates each and every record of the database following rigorous steps that include paper review, editing, and curation. At present, CTGA database curators create about 30 entries and update an equivalent number each month with an average of 5-10 publications reviewed per day. In order to allow a better chance for geneticists working on genetic disorders

in Arab individuals to contribute to the growth of the CTGA database, the CTGA database development team made available the CTGA database Information Submission Form (downloadable from http://www.cags.org.ae/ctgadisf.html) to speed up the process of data submission, review, and publication in the CTGA database. The proper utilization of the CTGA database Information Submission Form has contributed to the successful and rapid inclusion of many disease and gene records in the database straight from the pens of their corresponding authors, who are usually major authorities in their corresponding fields.

On the Types of Articles Reviewed for Data Collection

The types of papers usually obtained while collecting information from bibliographic indices or local peer-reviewed medical publications usually fall in the following categories:

1. Case reports: These are short and concise reports of individual or a handful number of cases. These reports usually include detailed descriptions of the diagnosis, treatment, and follow-up of an individual patient. They also contain some demographic information about the patient including age, gender, and ethnic origin.

2. Linkage studies: These are original articles that usually report the results of genetic linkage studies in a small number of families. Emphasis in these studies is more towards the genetic pathology rather than the clinical phenotype of a genetic abnormality.

3. Retrospective studies: These include several subtypes. Some retrospective studies may be focused on a specificdisorder or a group of genetic


disorders. Others may describe all patient cases reported at a medical institution during a certain period of time. This later group of studies usually results in a considerable amount of information regarding a large number of genetic disorders in certain populations with possibilities to also obtain prevalence rates of these disorders in the corresponding population.

4. Newborn screening studies: This refers to publications resulting from nationwide screening programs involving large numbers of cases screened within a specified period oftime. This type of articles is usually an important source of information on the prevalence rates of common genetic ailments in Arab populations.

5. Review articles: This is the least commonly targeted type of articles while collecting data for the CTGA database. Review papers do not include clinical data for genetic disorders or the details of individual patients. However, they are good starting points to seek further details regarding specific subjects.

Challenging Irregularities

Noteworthy is the consistent lack of information on the ethnic origin of patients with genetic disorders in many articles utilized to compile the CTGA database. These inconsistencies occur in both national and international reports; but are more numerous in the later group. In this aspect, it is important to adapt a unifiedsystem of clinical or molecular reporting that includes vital data necessary for population geneticists and ethnic database curators.

Science in the Arab World is generally suffering from serious lack of funds. For

this reason, science groups working in the highly demanding field of humangenetics conduct very limited studies that mostly result in clinical reports rather than molecular analyses. The majority of the already-small numbers of molecular studies are the fruits of collaborations with international groups that cover the needed expenses and provide the sophisticated equipment. Accordingly, large-scale data production of DNA or protein sequences, mutations, and single nucleotide polymorphisms (SNPs) is seriously lacking in the region and cannot be foreseen in the near future.

The CTGA Database Growth

Overall, all methods of data collection adapted by the CTGA database development team have resulted in a steady increase in the rate of total record numbers in the CTGA database since it was released late in 2004 and until present time. Two important soars mark the progress of data growth, these coincide with extensive efforts to thoroughly examine the genetic disorders observed in the Arab populations of the United Arab Emirates and Bahrain at the end of years 2004 and 2006, respectively (Figure 1.3).

Throughout this period, curation of the database and editorial decisions always took place at the Centre for Arab Genomic Studies to ensure the uniformity of the content and preserve the integrity of the database. Experiences gained from data collection projects in the United Arab Emirates and Bahrain will be used in the future to expand data collection activities to include other groups, institutes, and countries in a stepwise model. In conjunction with this process, necessary tools and techniques may also be developed to establish a unified and decentralized datacollection and authoring system to collect


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data from several countries at a time. When this system reaches full capacity, it will represent the largest attempt to definethe scale of genetic disorders described in the Arab World; a vast geographical area including 23 countries and inhabited by nearly 350 million individuals.

In order to cope with the growing numbers of records in the CTGA database, major enhancements were introduced to its search engine to allow the users to perform complicated queries and obtain focused results without sacrificing the simplicity. Detailed explanations and examples of how to use the Basic, Advanced, and Power Search modes at CTGA are available on the website of the database as well as in a recent publication of the Centre for Arab Genomic Studies (Tadmouri et al., 2006b).

Genetic Disorders in Arabs

As of October 2006, the CTGA database indicates the presence of 774 phenotype (disease) entries in Arab individuals (Table 1.2). Data on only about 275

related genes are available in the CTGA database indicating the emphasis given to clinical observations rather than molecular analyses in most of the research conducted in the region (Table 1.3).

In the initial release of the CTGA database in 2004, most of the records came from the Maghreb region (Tunisia, Morocco, and Algeria) as well as Lebanon and Saudi Arabia (Tadmouri, 2004b). Currently, this distribution has changed in favor of the United Arab Emirates, Palestine, Saudi Arabia, Lebanon, Tunisia, Bahrain, and Morocco (Figure 1.4). Different reasons explain this observation, mainly: the extensive surveys conducted to understand the extent of genetic disorders in the United Arab Emirates and Bahrain, the frequent encounter of articles from Palestine, Saudi Arabia, and Lebanon through international bibliographic indices, and the frequent article submissions received at the Centre for Arab Genomic Studies from scholars in Lebanon, Egypt, and Palestine. However, this distribution pattern is expected to further change as more extensive search projects will be conducted in the future to understand the magnitude of genetic

Figure 1.3. Total growth of CTGA database records from December 2004 until October 2006.


Table 1.2. Genetic disorders in Arab populations indexed in the CTGA database (October, 2006).


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disorders in Arab countries neighbouring the United Arab Emirates and Bahrain.

Classification of Genetic Disordersin Arabs

By employing the World Health Organiza-tion International Classification of Disease

version 10 (WHO ICD-10), it is possible to categorize the distribution of genetic disor-ders in the Arab World according to disease taxonomies (Figure 1.5). Nearly, one-third of genetic disorders in Arab individuals re-sult from congenital malformations and chromosomal abnormalities (34.4%). They are then followed by endocrine and meta-bolic disorders (18.2%) and diseases of the

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nervous system (10.2%). Other types of dis-orders do also occur in Arab population, yet, in lower frequencies.

Molecular Complexity of Genetic Disorders in Arabs

A detailed analysis of the molecular basis of defined genetic diseases indicatesthat approximately half of the genetic disorders described in Arabs result from single-gene or gene loci alterations (Figure 1.6). Hence, in the presence of the necessary technical infrastructure, diagnostic services may well be available for people at risk and preventive programs may be successfully applied in many Arab communities.

As expected, recessively inherited genetic disorders represent an overwhelming proportion of all genetic traits in Arab patients (Figure 1.7). High rate of consanguinity and the extended family structure, commonly present in Arab societies, are major factors to explain this observation.

The Spectrum of Genetic Disorders in Arabs

A relatively large number of new syndromes and variants were recently delineated in Arab people. Incidentally, Arab scholars were first to describesome of these disorders, such as: the Teebi type of Hypertelorism (Teebi,

Figure 1.4. Disease and gene records in Arab countries according to the CTGA database (October 2006).

Figure 1.5. Classification of genetic disorders in Arabs according to the WHO ICD-10 (October 2006).


1987), the Teebi-Shaltout syndrome (Teebi and Shaltout, 1989), Al-Gazali syndrome (Al-Gazali et al., 1994), and Megarbane syndrome (Megarbane et al., 2001). Alternatively, some other genetic disorders are Arab specific,such as: the Lebanese type of mannose 6-phosphate receptor recognition defect (Alexander et al., 1984), the Algerian type of spondylometaphyseal dysplasia (Kozlowski et al., 1988), the Kuwaiti type of cardioskeletal syndrome (Reardon et al., 1990), the Yemenite deaf-blind hypopigmentation syndrome (Warburg et al., 1990), the Nablus mask-like facial syndrome (Teebi, 2000), the Jerash type of the distal hereditary motor neuropathy (Christodoulou et al., 2000), Karak

syndrome (Mubaidin et al., 2003), and the Omani type of spondyloepiphyseal dysplasia (Rajab et al., 2004).

On the other hand, many genetic diseases exhibit specific geographical distributions. Examples include:

The Maghreb Region: Type II bare lymphocyte syndrome and the alpha erythrocytic 1 spectrin defect (Figure 1.8a).

North Africa: Type 2C of limb-girdle muscular dystrophy (Figure 1.8b).

The Middle East: Dyssegmental dwarfism (Figure 1.8c).

Figure 1.6. Distribution of genetic disorders in Arabs according to the number of causative gene loci (October 2006).

Figure 1.7. Classification of genetic disorders in Arabs according to mode of inheritance (October 2006).


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The Arabian Gulf: Laurence-Moon syndrome (Figure 1.8d), suppressor of tumorigenicity type 8 defect (Figure 1.8e), and type I primary hyperoxaluria (Figure 1.8f).

Other genetic disorders exhibit a wider geographical distribution encompassing one or more neighbouring regions, such as in the cases of the hemolytic-uremic syndrome (Figure 1.8g) and ankylosing spondylitis (Figure 1.8h). However, many genetic disorders indexed in the CTGA database exhibit sporadic distribution patterns over geographically separated regions in the Arab World. This is a strong indication about the necessity of conducting more research on these disorders to complete the picture. Candidate disorders for further research may include: alpha-thalassemia (Figure 1.8i), cystic fibrosis (Figure 1.8j),familial Mediterranean fever (Figure 1.8k), autosomal recessive polycystic kidney disease (Figure 1.8l), anencephaly (Figure 1.8m), Hirschsprung disease (Figure 1.8n), and others.

Alternatively, extensive published research available for certain genetic disorders reflects their wide presencein Arab populations. Examples of such disorders include: sickle cell disease (Figure 1.8o), beta-thalassemia (Figure 1.8p), and glucose-6-phosphate dehydrogenase deficiency (Figure 1.8q). The overwhelming distribution of these diseases in Arabs is best explained by the exposure of Arab countries to common

environmental factors that helped the natural selection for these disorders such as malaria in the case of hemoglobin disorders and dietary traditions in the case of glucose-6-phosphate dehydrogenase deficiency.

Final Notes

Approximately 32% of genetic disorders in Arabs remain confined to clinicalobservations with no significant attemptsto depict their molecular pathologies (data not shown). A large number of these disorders are confined to localfamily structures and were not described elsewhere. Mummifying these disorders at the clinical level represents a very serious loss for the global scientificcommunity to possibly depict the genetic nature underlying many disorders and permanently bury information regarding hundreds or thousands of human gene variants.

The knowledge gained from the study of the molecular pathologies leading to genetic disorders in Arabs could be immediately used to address urgent health needs. It would also offer an opportunity to promote education and knowledge drawing upon local examples, constructive engagement of global research efforts in human health from a position of strength, and opportunities to build sustainable research activity based upon education and the improvement of human health (Axton, 2006).



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Figure 1.8. Computer generated maps indicating the relative geographic distribution of some genetic disorders in the Arab World according to the CTGA database (October 2006).


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