1
GENETIC DISORDERS IN ARABS
Ghazi Omar Tadmouri
Centre for Arab Genomic Studies, Dubai, United Arab Emirates
Historical Primer
Genetic and inherited disorders have accompanied humanity since its earliest existence. Many prehistoric
and historic sites have revealed archeological
remains with pathologies suggestive of inherited
disorders. Paleopathology studies - the identification
of pathological conditions in ancient skeletal remains
- from many world sites revealed the presence of
various hereditary or congenital conditions including
Paget’s disease, neurofibromatosis, cleft lip and cleft
palate, juvenile kyphosis (Scheuermann’s disease),
scoliosis, spina bifida, achondroplasia, Hurler syndrome
(mucopolysaccharidosis type I), Hunter’s syndrome,
(mucopolysaccharidosis type II), Morquio’s syndrome
(mucopolysaccharidosis type IV), osteogenesis imperfecta
(types III and IV), cleidocranial dysostosis, osteopetrosis,
diaphyseal sclerosis (Camuratoi-Engelmann disease),
osteopoikilosis, and many others (reviewed in Ortner,
2003). One of the oldest of such records includes a 1.5
million year old fossil of a 2-year-old Homo erectus child
with amelogenesis imperfecta (Zilberman et al., 2004).
In Indonesia, the skeleton of a 25-30 year-old Homo
floresiensis, discovered in 2003 on the island of Flores,
featured a small skull that could be due to microcephaly
(Jacob et al., 2006). In Egypt, scientific investigation of
mummies from the huge necropolis of Thebes-West in
Upper Egypt revealed osseous manifestations suggestive
of metabolic and chronic anemia in high frequencies in
populations of the “Middle Kingdom” (2050-1750 BCE;
Nerlich et al., 2002). In addition, bizarre physical features
were shared by many members of Egypt’s 18th Dynasty,
including the Pharaoh Akhenaten, suggestive of possible
familial disorders possibly including the aromatase
excess syndrome, the sagittal craniosynostosis syndrome,
or a variant of the Antley-Bixler syndrome (Braverman et
al., 2009). Interestingly, ancient DNA analysis revealed
a b-thalassemia mutation in the skeletal remains of an
Ottoman child with severe porotic hyperostosis (Filon et
al., 1995).
Concomitantly, almost all prehistoric and ancient
civilizations suffered from the severe consequences
of many infectious diseases. In fact, many of these
diseases played major roles in the development of human
civilization, impacting and altering the course of wars,
migrations, population growth, and urbanization. In many
world countries, including Arab States, breakthroughs
in managing such diseases only happened few decades
ago with the clinical availability of specific drugs and
vaccines. This progress decreased the impact of such
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GENETIC DISORDERS IN THE ARAB WORLD QATAR
disorders in favor of an increased understanding of the
molecular basis of heredity, hence, a better recognition
of genetically transmitted conditions as a major cause of
morbidity and mortality (Tadmouri, 2008).
Genetic Disorders in World Populations
To date, records for more than 6500 inherited disorders,
known to afflict world populations, are indexed and
maintained at the Online Mendelian Inheritance in Man
(OMIM) database, which is a comprehensive compendium
of human genes and genetic phenotypes (McKusick,
2007). Many of these disorders are rare entities that
occur at higher frequencies in particular ethnic, racial,
or demographic groups. More common disorders show
a worldwide spread supported by natural selective forces
or stimulated by socially-oriented reproductive choices.
Systematic attempts to catalogue genetic disorders in
world populations are almost non-existent. The only
available examples include the Finnish Disease Database
(www.findis.org; 35 disorders) and Rare Diseases Sweden
database (www.sallsyntadiagnoser.nu; 68 disorders)
that represent national efforts to highlight the disease
heritage of their respective populations. Hence, to try
to give an approximate visualization of the number of
genetic disorders in various world populations the only
comprehensive source that could be utilized would be
the OMIM database. Using proper search syntaxes it
is possible to deduce the populations in which most of
the genetic disorders were described; these include: the
Japanese (~750), Italian (~550), German (~450), Turkish
(~400), Chinese (~350), Canadian (~300), French
(~300), Finnish (~300), Pakistani (~300), and many
other populations. However, this strategy only gives a
rough estimate on the number of genetic disorders in a
population with possibly very large deviations from actual
figures (reviewed in Tadmouri, 2008).
Arab Populations: A Definition
Defining the term Arab is a challenging task. Arabs
are a panethnicity of peoples of various ancestral
origins, religious backgrounds, and historic identities.
Linguistically, Arab populations encompass a vast
geographical region that extends from south of Iran in
the east to Morocco in the west, including parts in the
southeast of Asia Minor, East Africa, and West Africa.
However, the political definition of Arab populations is
Major Prehistoric Events
Archeological excavations and historical records provided
considerable information regarding early evolutionary
history of modern humans in this vast geographical region.
However, the application of DNA molecular anthropology
methods allowed scientists to high resolution information
that go as far as depicting similarities and dissimilarities
between the population histories of males and females by
analyzing unique non-recombining regions of uniparental
Y-chromosome and mitochondrial DNA (mtDNA),
respectively.
DNA evidence indicates that modern humans originated
in East Africa about 100,000-200,000 years ago (Liu
et al., 2006) then established regional populations
throughout the continent.
Archeological artifacts
excavated from Taforalt in Morocco indicate that human
inhabitation of modern day’s Maghreb region (modern
day Morocco, Algeria, Tunisia, and Libya) date back to
some 82,000 years ago (Ferembach, 1959). At that time,
settlements in the region were characterized by developed
cultural manifestations that could only exist in Europe
40 millennia later (Bouzouggar et al., 2007). According
to the Recent Out-of-Africa model, members of one
branch of anatomically modern humans left Africa to the
Near East some 60,000-70,000 years ago (Relethford,
2008). Phylogenies constructed on the basis of mtDNA
comparisons are indicative for two possible migration
routes in this episode of human history:
(1)One route laid across Bab-el-Mandeb straits in the Red
Sea linking modern day Eritrea and Djibouti in Africa
to eastern Yemen in the Arabian Peninsula (Bailey et
al., 2007; Cerny et al., 2008). Supportive evidence
comes from Y-chromosome diversity studies that
show a pool typical of African biogeographic ancestry
among 14% of modern Saudi males (Abu-Amero et al.,
2009). High diversity in the Y-haplogroup substructure
in samples from the region extends the geography of
this active route to include Yemen, southern Arabia,
South Iran, and South Pakistan. This route maintained
its important role in influencing gene flow from Africa
along the coastal crescent-shaped corridor of the Gulf
of Oman facilitating human dispersals into the region
until nearly 2500 years ago (Cadenas et al., 2008).
(2)Another route followed the Nile from East Africa,
heading northwards and crossing through the Sinai
Peninsula into the Levant resulting in a marked gene
flow especially during the Upper Paleolithic and
Mesolithic periods between 14,000-40,000 years
ago (Cann et al., 1987; Ingman et al., 2000; Luis
et al., 2004). Human populations in the Near East
then branched in several directions, some moving
into Europe and others heading east into Asia (Ke et
al., 2001; Maca-Meyer et al., 2001; Underhill et al.,
2001; Lahr and Field, 2005). Y-chromosome analysis
support this view and demonstrate the absence of
any significant genetic barrier in the eastern part of
the Mediterranean area, where a remarkable genetic
variation was attained and gene flow followed the
“isolation-by-distance” model. This is in contrast to
a strong north-south genetic barrier, for both male and
female gene flow, in the western Mediterranean basin,
defined by the Gibraltar Strait (Manni et al., 2002;
Ennafaa et al., 2009).
Paleoanthropological evidence and mtDNA variation
analysis indicate that both the Horn of Africa and,
possibly more importantly, the Levantine corridor served,
repeatedly, as migratory passageways between Africa and
Eurasia (Luis et al., 2004; Rowold et al., 2007). Some
studies also support the view that regions near, but external
to northeast Africa, like the Levant or the southernArabian Peninsula could have served as incubators for the
early diversification of non-African lineages (Abu-Amero
et al., 2009).
GENETIC DISORDERS IN ARABS
more conservative as it only includes those populations
residing in 23 Arab States, namely: Algeria, Bahrain,
Comoros, Djibouti, Egypt, Eritrea, Iraq, Jordan, Kuwait,
Lebanon, Libya, Mauritania, Morocco, Oman, Palestine,
Qatar, Saudi Arabia, Somalia, Sudan, Syria, Tunisia,
United Arab Emirates (UAE), and Yemen. Yet, this
geocultural unit is the largest in the world after Russia and
Anglo-America, with a population exceeding 360 million
and spanning more than 14,000,000 square kilometers
(Appendix 1).
The Early Farmers
Around 12,000 years ago, Neolithic human populations
adapted agricultural technologies that allowed them
to establish permanent sizeable settlements and to
adapt a far-reaching shift in subsistence and lifestyle.
Undoubtedly, improvement of the climatic conditions
in the area along with the practice of agriculture helped
in the establishment of major historical settlements with
sizeable densities that could have contributed enormously
to the genetic makeup of modern Arab populations. Yet,
farming was almost always associated with settlements
near mosquito-infested soft and marshy soil causing large
malarial outbreaks (Grmek, 1994; de Zulueta, 1994; Joy
et al., 2003). These outbreaks imposed selective pressure
on the human genome and amplified the frequencies of
several genetic disorders including sickle cell disease,
b-thalassemia, and glucose-6-phosphate dehydrogenase
(G6PD) deficiency (Angel, 1966; Carter and Mendis,
2002; Kwiatkowski, 2005).
In the Arabian Peninsula, Levantine, Sub-Saharan African
and Iranian lineages have participated in the building of
the primitive Arabian population. Approximately 6269% of today’s Y-chromosome and mtDNA haplogroups
in Saudi Arabia share common structures with those in the
near east and demonstrate an important role for the Levant
in shaping the Neolithic dispersal of human settlements
in the Gulf. Male lineage estimates for these prominent
Levantine haplogroups indicate a north to south influence
with a history of almost 12,000 years in Saudi Arabia,
GENETIC DISORDERS IN THE ARAB WORLD QATAR
11
11,000 years in Yemen, mainly in the western region, and
only at nearly 7,000 years in Qatar and the UAE (AbuAmero et al., 2008; Cerny et al., 2008; Abu-Amero et al.,
2009). Detailed analyses hint to a terrestrial more than to
a maritime colonization for the eastern Arabian Peninsula
that was followed by subsequent population isolation
from the western Arabian Peninsula which demonstrates
significant genetic affinities to near-eastern populations
(Alshamli et al., 2009). On the other hand, studies of
mtDNA variability confirm a notable sub-Saharan African
and, to a lesser extent, Iranian female-driven flow in the
Arabian Peninsula (Rowold et al., 2007; Cerny et al., 2008).
Analysis of the pattern of Y-chromosome and mtDNA
variations in North Africa provides evidence of the
relatively young population history of North Africa
mainly formed through a strong demic expansion of
Neolithic pastoralists from the Levant (Arredi et al.,
2004; Kujanova et al., 2009). Some of these earliest
civilizations in the Maghreb region include immigrant
Berbers who originated from the Sahara 10,000 years
ago and left considerable gene imprints in the gene pool
of modern day Mauritania, Morocco, Algeria, Tunisia,
Libya, and southern Egypt (Lucotte et al., 2000; Lucotte
and Mercier, 2003). The Berbers were followed by the
Mesolithic Capsians who settled in the area 2,000 years
later (Irish, 2000).
1
Major Events in Ancient and Medieval History
In the Arabian Peninsula, Semitic-speaking peoples of
Arabian origin migrated into the valley of the Tigris and
Euphrates rivers in Mesopotamia some 7,000-5,500 years
ago (Beech et al., 2005). Archeological evidence further
indicates that another group of Semites left Arabia around
4,500 years ago during the Early Bronze Age and settled
along the Levant mixing in with the local populations
there. Some 3,500 years ago, the Phoenician civilization
of Lebanon became a developed enterprising maritime
trading culture. Subsequently, Phoenician traders spread
across the Mediterranean and established major cities and
colonies that harbored their pathologic or polymorphic
gene variations (Walter et al., 2001; Tadmouri et al.,
2001; Gerard et al., 2006; Zalloua et al., 2008a). Results
of the Genographic Consortium from Y-chromosome
variations indicate that as many as 1 in 17 men living
today on the coasts of North Africa and southern Europe
may have a Phoenician direct male-lineage ancestry
(Zalloua et al., 2008b). The genetic pool was further
enriched in Mesopotamia through Persians while Romans
gained a 600 year-long period of settlements throughout
most of the region and were subsequently replaced by the
Byzantines (Zahed et al., 2002).
Soon after the rise of Islam 1,400 years ago, the Arab
Caliphates unified the entire region as a distinct territory
and amalgamated the dominant ethnic identity that persists
today in the Levant and extends as far as the Maghreb
Region in North Africa as well as Andalusia in the Iberian
Peninsula (Fattoum and Abbes, 1985; Ben Abdeladhim et
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GENETIC DISORDERS IN THE ARAB WORLD QATAR
al., 1987; Zalloua et al., 2008a). Similarly, the Arabian
Peninsula linked distant populations of China and India to
communities of the Mediterranean and beyond. During
this period, demographical dynamics were predominantly
governed by cultural change in endogenous populations
rather than demic influences with significant gene flow
(Labie et al., 1994). This view is strongly supported by
Y-chromosome analysis of Muslim expansion in India
and mtDNA haplogroups in the Sinai Peninsula and North
Africa (Salem et al., 1996; Gutala et al., 2006; Ennafaa
et al., 2009).
On the contrary, the eastern Mediterranean region
witnessed major Crusader settlements during the 11th-13th
centuries CE that could have caused remarkable genetic
drifts and bottlenecks and introduced western European
lineages into the Levant affecting a considerable portion
of today’s gene pool (Zalloua et al., 2008a). The impact
of western European gene backgrounds extends to the
eastern Arabian Peninsula where major parts, including
Bahrain, fell under the influence of the Portuguese at the
beginning of the 16th century and remained as such for the
following 150 years. This presence left clear impressions
in the mutational spectrum of common disorders in the
eastern Arabian Peninsula as in the case of the relative
high frequency of the western Mediterranean Codon 39
(C-T) b-thalassemia mutation (Gomes et al., 1988; Jassim
et al., 1998; Al-Ali et al., 2005; reviewed in Tadmouri
and Gulen, 2003). On the contrary, some other disorders
spread out to geographically distant locations from the
region under this Portuguese influence; for example,
as demonstrated in the increasing evidence noted with
regard to Machado-Joseph disease (Purdey, 2004; Mittal
et al., 2005).
Landmarks of Modern History
Simultaneously, Ottomans controlled much of the
Mediterranean then expanded their influence to cover
all the Arabian Peninsula and further contributed to the
enrichment of the genetic pool in the region (Haj Khelil et
al., 2004). After the 19th century, areas of the Maghreb
were colonized by France, Spain and Italy while the
remaining areas where colonized by France and England.
Despite all this long trail of admixtures in the region,
there are still localities marked by the presence of genetic
isolates. Some examples include the dwellers of the Dead
Sea region in Jordan (Gonzalez et al., 2008), Bedouins of
Sinai (Salem et al., 1996), and inhabitants of the Island of
Jerba in Tunisia (Loueslati et al., 2006).
Arab Diaspora
Throughout modern history, Arab emigrants formed
many Diasporas in world continents. At present, the
main countries of immigration within the Arab World
are countries of the Gulf Cooperation Council that host
more than two million emigrant Arabs mostly from Iraq
In Latin America and the Caribbean, there is an estimated
presence of more than 16 million people of Arab
(Lebanese, Syrian, and Palestinian) descent according
to statistics compiled by the Arab Federation of Latin
America (Salloum, 2000; Luxner, 2001). In Brazil, the
Arab community started arriving over one hundred years
ago. Brazil has nearly 10-12 million Brazilians of Arab
ancestry, mainly from Lebanon, Syria, Palestine, and Iraq
(Luxner, 2005). Brazilians of Lebanese ancestry number
nearly seven million, and some 70% of them live in Sao
Paulo, while Brazilians of Syrian origin number nearly
three million (Klich, 1992). In Argentina, estimates
indicate a net Arab migration to Argentina that is not
less than 110,000 immigrants between years 1871-1976.
Today, Argentina is home for large Arab communities;
including not less than 1,000,000 of Lebanese descent.
In Mexico, approximately 400,000 people are from
Lebanese background and represent nearly 45% of all
Arab Mexicans (Guzman and Zeraoui, 2003). In addition,
substantial minorities, mainly from Lebanon, Syria, and
Palestine, are also found in Chile (800,000 including
nearly half a million of Palestinian descent, 170,000 from
Syria, 30,000-90,000 from Lebanon, and 10,000 from
Jordan), Venezuela (600,000 including nearly 340,000400,000 of Lebanese and significant communities
originating from Syria, Palestine, and Iraq), Colombia
(200,000 of Lebanese descent, 40,000-70,000 of Iraqi
descent, and 12,000 of Palestinian descent), El Salvador
(150,000 of Palestinian descent), Uruguay (55,000 of
Lebanese descent), Honduras (54,000 of Palestinian
descent), Puerto Rico (25,000 of Iraqi descent), Ecuador
(20,000-100,000 of Lebanese descent), Haiti (4,600
mainly of Lebanese and Syrian descent), Bolivia, Costa
Rica, Dominican Republic, Guatemala, Guinea, Jamaica,
and Trinidad and Tobago (Salloum, 2000; Luxner, 2001).
In North America, Arabs arrived in several waves of
immigrations from countries of southwestern Asia
(Lebanon, Syria, and Palestine) and North Africa
(Morocco, Algeria, and Egypt) since the 1880s (The
Canadian Arab Federation, 1999; Zogby International,
2000). Approximately 110,000 Arab-speakers gained
entry to the US prior to year 1914 and some 18,500
between years 1915 and 1940. In between years 1945
and 1952, 7,285 Arab immigrants, mainly from Palestine,
Syria, Egypt, and Lebanon, were admitted (Aboud, 2002).
Today, there are around 3.7 million people in the United
States of Arab ancestry mostly from Lebanon, Syria,
or Palestine (Zogby International, 2000). Lebanese
Americans constitute a greater part of the total number
of Arab Americans residing in most states (37%), except
New Jersey, where Egyptian Americans are the largest
Arab group (12% of all Arab Americans; The United
States Census Bureau, 2000). Americans of Syrian descent
make up the majority of Arab Americans in Rhode Island
(12% of all Arab Americans), while the largest Palestinian
(68,000) and Iraqi populations are in Illinois (6% and
3% of all Arab Americans, respectively). Other Arab
groups residing in the United States come from Jordan,
Morocco, Yemen, Algeria, Saudi Arabia, Tunisia, and
Libya. In year 2000, 27% of the Arab population lived
in the Northeast, while 26% lived in the South, 24%
in the Midwest, and 22% in the West. Approximately,
70,000 people of Arab ancestry live in New York, making
it the city with the largest number of Arabs, followed by
Los Angeles, Chicago, Houston, Detroit, and San Diego
(The United States Census Bureau, 2000). In Canada,
5,899 Syrian and Arabian immigrants were admitted up
to year 1914 while approximately 2421 were admitted
between years 1915 and 1940 and 1761 were admitted
between years 1945 and 1955 (Aboud, 2002). Today,
most of the 470,580 Arabs living in Canada reside in
Quebec (42%) and Ontario (42%; Statistics Canada,
2006). Arab communities in Canada are highly urban;
69% live in Toronto, Montreal, and Ottawa-Hull alone.
They mainly originate from Lebanon (250,000-400,000
people), Morocco, Algeria, Egypt, Syria, Palestine, and
others (The Canadian Arab Federation, 1999).
GENETIC DISORDERS IN ARABS
(more than 4 million), Palestine (300,000), Lebanon
(120,000), Egypt, and Syria. In the year 2007, the United
Nations High Commissioner on Refugees estimated that
over 2.2 million Iraqis had been displaced to neighboring
countries, with up to 100,000 Iraqis fleeing to Syria and
Jordan each month. Outside the Arab World, the largest
Arab communities live in Latin America, the Caribbean,
North America, Europe, parts of Southeast Asia, Australia,
and West Africa.
In Europe, the history of Arab immigrations started as
early as 1898 with the arrivals of Somali and Yemeni
communities to the United Kingdom. Today, the United
Kingdom is home for about 1 million Arabs representing
1.7% of the country’s population. The vast majority of
these originate from Iraq (250,000-450,000), Yemen
(70,000-80,000), Morocco (65,000-70,000), Algeria
(40,000), and Egypt (some 30,000; Office for National
Statistics, 2001). Yet, the European country with the
largest number of Arab immigrants is France, with nearly
7 million Arabs, including a great majority of nearly
3 million from North Africa (including 1,200,000 of
Moroccan origin) and around 100,000-250,000 Lebanese.
The region with the largest Arab community in France
is Île de France (Paris). On the other hand, the number
of Arab immigrants in Germany is 280,000-350,000
(including 150,000 Iraqis and 50,000 Lebanese) and
in Belgium there are approximately 333,000 Arabs. In
the Netherlands, official statistics indicate the presence
of not less than 350,000 Arabs of Moroccan origin with
a significant presence of many Iraqis as well (Centraal
Bureau voor de Statistiek, 2010). Further to the North,
Sweden hosts about 120,000 Iraqis forming the country’s
second largest immigrant group. Other major groups of
Arab descent in the country include Lebanese (23,000),
Syrians (20,000), and Moroccans (7,000; Statistics
Sweden, 2010). In Eastern Europe, Bulgaria is home
for about 17,000 Arabs mainly from Lebanon, Syria,
Palestine, and Iraq (Zhelyazkova et al., 2005). Other
European countries with significant Arab communities
include Turkey (60,000-90,000 Iraqis), Norway (26,000
Iraqis), Greece (5,000-40,000 Iraqis), Denmark (12,00015,000 Iraqis), Belarus, Italy, Romania, and Spain.
GENETIC DISORDERS IN THE ARAB WORLD QATAR
13
In Southeast Asia, most of the prominent Indonesians,
Malaysians and Singaporeans of Arab descent have their
origins in the southern part of the Arabian Peninsula,
especially the coastal Hadhramaut region of Yemen and
Oman. Estimates indicate that as many as 4 million
Hadramis live in Indonesia and 7,000-10,000 are in
Singapore (Talib, 1997). Hadramis also contributed to the
strong presence of a large Arab population in Hyderabad
in India, known as Chaush, who migrated to the subcontinent in the 18th century and were once the soldiers of
the Nizam of Hyderabad (Minda, 2004). Similarly, many
Arab traders permanently settled in southern India and in
Sri Lanka between the 8th and 15th centuries. Descendents
of these traders formed the bulk of today’s Sri Lankan
Moors, the third largest ethnic group in the country with a
population of not less than one million (Ross and Savada,
2002). In Afghanistan, Arab presence dates back to the
end of the 7th century, when Umayyad armies overran
the Sassanids in Nihawand. Arabs remained a minority
in the conquered lands, but set up garrison towns to
house regional armies and were the main force in many
important urban centers. Historical references from the
second half of the 18th century point out that the lineages
of not less than 60,000 families trace back to Arabic
tribes that came from Khorasan under the Umayyads and
Abbasids (Kieffer, 2000).
1
In Australia, Arabic is the fourth most widely spoken
second-language. Syrian and Lebanese-born immigrants
started arriving to the continent as early as 1911 (1527
persons). In year 1921, the Arab population grew to
1803 individuals then in year 1933 to 2020 persons. In
between years 1945 and 1955, 4,053 new settlers arrived
to Australia from Lebanon, Syria, and Egypt (Aboud,
2002). Today, the Arab community in Australia includes
roughly 360,000 people from Arab countries (Australian
Bureau of Statistics, 2006). Some estimates place the
number of Australians of Arab origin at almost one
million from which more than 500,000 are from Lebanese
descent. Of the Arabs who have settled in Australia, the
Lebanese and Egyptian communities are generally the
most established, followed by the Iraqi (nearly 80,000)
and Syrian communities (Australian Government, 2003).
The Lebanese in Australia are heavily concentrated in the
larger cities, with Sydney being home to some 75% of
Australia’s Lebanese; and nearly to 45% of Australia’s
Arabs (Price, 1999). In neighboring New Zealand,
Lebanese makes up a majority of Arabs in the country
with a population of nearly 47,200 individuals (Akoorie,
2007).
Arab Diasporas are also noted in several countries in
Central and West Africa (Handloff, 1988). Although
there is debate about the exact year during which Arabs
first arrived in West Africa, it is generally believed that
the Lebanese might have been the earliest immigrants
to arrive to the region between the 1860s and 1870s
(Boumedouha, 1993). Main African countries with
notable Arab communities include Ivory Coast (home
to over 300,000 Lebanese and Syrians; Handloff, 1988),
Senegal (roughly 30,000 Lebanese), Sierra Leone
14
GENETIC DISORDERS IN THE ARAB WORLD QATAR
(roughly 10,000 Lebanese), Liberia, and Nigeria (Van der
Laan, 1993).
Demographic and Medico-Economic Characteristics
of Arab Populations
Although Arabs may share a commonality of language,
history and religion, their societies are at variance
when it comes to demographic and medico-economic
characteristics. Some of the aspects that markedly affect
the prevalence and natural history of genetic diseases in
the Arab World include:
• High fertility rates (1.7-6.4 children born/woman;
Appendix 1).
• High birth rates (15-43 births/1,000 people; Appendix
1).
• High annual population growth rates of 0.6-3.6%
(Appendix 1).
• Extremely high rates of birth defects (63-82/1000 live
births; Christianson et al., 2006).
• High rates of inbreeding or consanguineous marriages
(Tadmouri et al., 2009).
• Child bearing at either very early or old maternal ages.
• The presence of isolates (e.g., Armenians, Bedouins,
Druzes, Jews, Kurds, and Nubians).
• The lack of public health measures directed toward
control and prevention of congenital and genetically
determined disorders.
Health Care in the Arab World
Despite the alarming demographic characteristics,
unprecedented achievements have been especially
prominent in the health care sector during the last few
decades in almost all Arab countries. Improvements have
been reflected by the reducing rates of infant mortality
below the global average of 44.1 per 1000 live births,
the increasing rate of literacy far beyond the global
level of 82% of total populations, and the increase in
life expectancies beyond the global level of 66.1 years
(Appendix 1). This is a natural outcome of increasing
investments in healthcare systems in the region. However,
these improvements will only solidify once attention is
focused on basic health problems, as well as on underlying
factors such as poverty. As matters currently stand,
many factors combine to undermine commitment to such
priorities including rapid population growth and urban
expansion, spiraling health and medical costs, fascination
with high-tech medicine and sophisticated high-profile
hospitals, and inappropriate medical education and
emigration of trained personnel (Stephen, 1992). To
overcome these obstacles, medical genetic societies in
the region have an important role to play in establishing
an interactive process of dialogue and discussion to be
directed towards the public and decision makers. This
process should include the establishment of preventive
programs acceptable by target populations as a main goal
besides tackling related issues of local importance.
Currently, genetic services in the region can be broadly
grouped as: national screening programs, genetic
testing laboratories, and research centers. With nearly 9
million infants estimated to be born annually, advanced
national screening programs exist in almost all Arab
States with the aim of routine screening for commonly
occurring genetic ailments at the newborn and premarital
levels (Saadallah and Rashed, 2007). Genetic testing
facilities, however, have more limited coverage and are
usually maintained at private institutions with variable
capacities. In research centers, mostly found within
academic or semi-governmental setups, activities are
usually translated into scientific peer-reviewed reporting
that, so far, occupies only a small share (nearly 0.5%)
of the permanent record of global scientific progress
(Tadmouri and Bissar-Tadmouri, 2003). Among active
research centers in the field are King Faisal Specialist
Hospital and Research Centre in Saudi Arabia, the
National Research Center in Egypt, the Medical Genetics
Unit at Saint-Joseph University in Lebanon, the Kuwait
Medical Genetics Centre, Institut Pasteur in Tunisia, the
Hereditary Research Laboratory at Bethlehem University
in Palestine, the UAE University, Weill Cornell Medical
College in Qatar, and Al Jawhara Center for Genetics and
Inherited Diseases in Bahrain, just to name a few.
Outlook of Genetic Research in the Region
Science in the Arab World is generally suffering from
serious lack of funds. In many instances, science
groups working in the highly demanding field of human
genetics conduct very limited studies that mostly result
in clinical reports rather than molecular analyses
(Tadmouri and Bissar-Tadmouri, 2003).
Despite
this, the region witnessed in the last 10 years a steady
increase in biomedical research outputs mainly driven
by stringent academic promotion requirements, the
foundation of many advanced research centers, the
launch of several national and private funding agencies
supporting biomedical research activities, and the “return
migrations” of Arab scientists educated in world-class
institutions. This category of scientists is characterized
by higher publication rates, extensive contacts distributed
over distant geographical locations, and the expertise
to conduct advanced genetics research. Many of these
observations can be benchmarked using comprehensive
online bibliographies that allow mapping of complete or
near-complete co-authorship networks for entire fields and
provide a window on patterns of scientific collaboration
in region.
Overall, there is a rising incidence of co-authorship in
many academic disciplines. This is largely driven by
the dynamics of internal differentiation of science into
specialized disciplines and large scale investment in
science enhancing multi-national collaborations (i.e., ‘big
science’). At global level, biological sciences lead this
trend with an average co-authorship rate of 3.75 when
studying nearly 2 million papers published in years 19951999 (Newman, 2004). By analyzing approximately
52,000 PubMed-indexed biomedical articles published by
principal investigators from Arab countries for the years
1988-2007, an average of 3.9 co-authors is observed in
each published article. Sizes of co-authorship patterns in
Jordan, Saudi Arabia, Egypt, and Kuwait are in the range
of 3 co-authors, while these units reach sizes of 4-6 coauthors in Lebanon, Morocco, and Tunisia (unpublished
results). By analyzing a subset of 566 random genetics
publications indexed in the Catalogue for Transmission
Genetics in Arabs (CTGA) Database for genetic disorders
in Arab populations, the average co-authorship rate
increases to 5.7 indicating that Arab scientific reporting in
medical and molecular genetics is generally a collaborative
activity due to the interdisciplinary requirements to
achieve comprehensive phenotype-genotype correlations
and the expense of modern molecular technologies
(unpublished results).
GENETIC DISORDERS IN ARABS
Medical teaching in the region is deep-rooted.
Unsurprisingly, many Arab States are home to some of
the oldest medical schools such as Qasr Al-Aini Medical
School and Teaching Hospital in Egypt (1827), the
American University of Beirut Medical Center (1867),
the Syrian University (1923), the Kitchener School of
Medicine in University of Khartoum (1924), and the
Iraqi Royal College of Medicine (1928). Yet, that has
led many schools in the past to follow classical curricula
that resulted in many practitioners in the region having
an incompletely assimilated understanding of heredity.
This reflected in the absence of proper genetic counseling,
in many communities, and in the genetic literacy at the
levels of the general public and at-risk families as well.
However, the leaping progress achieved in medical
genetics in the past few decades transformed this science
from a peripheral entity into a central innovative area
with extensive interdisciplinary exchange. Over the
last few decades, medical genetics established itself as a
core pillar in many Arab academic medical educational
systems. This has lead to an increased understanding of
the molecular basis of heredity and to a better recognition
of genetically transmitted conditions as a major cause of
morbidity and mortality in Arab States.
The analysis of resulting medical genetics networks over
the last two decades reveals important observations on
how some Arab States, such as Tunisia, Morocco, and
Lebanon, integrated themselves further close to the core
of more advanced countries, namely France and the USA
(Wagner and Leydesdorff, 2005). Within this group,
research collaborations, mostly international, involve the
implementation of advanced molecular technologies and
result in papers with higher visibilities. In fact, the most
recent survey conducted by the Centre for Arab Genomic
Studies on articles discussing genetic disorders in Arab
patients indicate that gene-pathology articles constitute
only 28% of the total number of articles analyzed
(Tadmouri, 2008). Maghreb countries (i.e., Algeria,
Tunisia, and Morocco) are leading in terms of molecular
genetic studies (Figure 1.1). In many cases, these
molecular studies are the fruits of collaborations with international groups that usually cover the needed expenses
GENETIC DISORDERS IN THE ARAB WORLD QATAR
15
and provide the sophisticated equipment (Selamnia and
Tali-Maamar, 2003; Dakik et al., 2006). As an example,
careful investigation of corresponding research articles
indicate the significant role of French science groups in
diagnosing disorders in Algerian, Tunisian, or Moroccan
patients living in France (Tadmouri and Bissar-Tadmouri,
1999). Meanwhile, Eastern Mediterranean and Gulf
Arab countries became more structured, but disconnected
from the main grouping of more advanced countries
(Wagner and Leydesdorff, 2005). This trend seems to be
fuelled by collaborations at the clinical level that address
endogenous needs through local capacities. For example,
in countries for which the Centre for Arab Genomic
Studies concluded its exhaustive surveys on genetic
disorders (i.e., UAE, Bahrain, Oman, and Qatar) the
percent share of molecular studies ranges only between
14-16% of the total of medical genetics. 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.
1
On the bright side, however, noteworthy achievements do
also exist in the region. Recently, a scientific team from
Al Jawhara Center for Molecular Medicine, Genetics,
and Inherited Disorders at the Arabian Gulf University
isolated a new protein called ISRAA (Immune System
Released Activating Agent), which represents the first
molecule that acts as a mediator between the central
nervous system and the immune system. This protein is
produced in the spleen when the host is infected. It then
activates the immune system and gives it the capability to
fight against the infection. This unprecedented discovery
may help to find a possible cure for killer diseases
including AIDS and cancer (Bakhiet and Taha, 2008).
Studies are now being developed to study expression
analyses of related genes as well as functional studies of
possibly associated proteins (Bakhiet and Taha, 2008).
In Oman, Sultan Qaboos University in collaboration with
several international institutions established a research
Figure 1.1. Schematic representation of the per cent generelated articles of the total number of biomedical records
surveyed at the Centre for Arab Genomic Studies (July 2010).
16
GENETIC DISORDERS IN THE ARAB WORLD QATAR
program called “Oman Family Study”. The aim of this
program is to establish an Omani model for the study
of the genetics of complex diseases, such as diabetes,
obesity, dyslipidemia, and hypertension. Individual
studies in this program resulted in identifying several
loci that may be implicated in the pathogenesis of these
diseases (Bayoumi et al., 2008). Similarly, the Molecular
Pathology Unit at the University of Kuwait specializes in
studying genomic aspects of early-stage colorectal cancer
and breast cancer and aims at translating its discoveries
into diagnosis, screening, premarital counseling of
couples, and prenatal diagnosis of offspring with biallelic
cancer gene mutations (Al-Mulla et al., 2006; Marafie et
al., 2009; Al-Mulla et al., 2009). In Qatar, the Shafallah
Medical Genetics Center is focusing on linkage analysis
and mutation spectrum definitions for common and rare
disorders occurring in the Arab population of Qatar (AbuAmero et al., 2008; Ahram et al., 2009). Likewise, in
Bethlehem University genomic analyses conducted over
extended consanguineous families have resulted in the
determination of multiple novel alleles for inherited hearing
loss in the Palestinian population (Walsh et al., 2006).
Consanguinity in Arab People
Many Arab countries display some of the highest rates
of consanguineous marriages in the world (Table 1.1).
Sociocultural factors, such as maintenance of family
structure and property, ease of marital arrangements,
better relations with in-laws, and financial advantages
relating to dowry, play a crucial role in the preference
of consanguinity in Arab populations (Tadmouri et al.,
2009).
In Arab populations, consanguinity rates are changing
in either way. In Bahrain, Egypt, Iraq, Jordan, Kuwait,
Lebanon, Libya, Palestine, and Tunisia decreasing trends
of consanguineous marriages have been recorded among
previous and present generations. On the other hand,
increasing consanguinity rates have been recorded among
generations in Algeria, Morocco, Oman, Qatar, Saudi
Arabia, Sudan, Syria, the UAE, and Yemen (reviewed in:
Tadmouri et al., 2009).
In Arab populations and Diasporas, the deep-rooted
norm of consanguineous marriage has been widely
accused of being an important factor contributing to the
preponderance of autosomal recessive genetic disorders
(reviewed in: Tadmouri et al., 2009). Actual data from
countries for which surveys on the occurrence of genetic
disorders have been completed by the Centre for Arab
Genomic Studies (Bahrain, Oman, Qatar, and the UAE)
indicate that recessive disorders are greater in number
than the dominant ones. Interestingly, these data
demonstrate a direct correlation between the increase in
consanguinity rates in a population accompanied with an
increase in the share of autosomal recessive disorders and
a decrease in the number of autosomal dominant disorders
in the respective population (reviewed in: Tadmouri et al.,
2008).
Country
>1C, 1C
Overall Consanguinity
Algeria
Bahrain
Egypt
Nubia
Iraq
Jordan
Kuwait
Lebanon
Libya
Mauritania
Morocco
Oman
Palestine
Qatar
Saudi Arabia
Sudan
Syria
Tunisia
United Arab Emirates
Yemen
11.3
11.4-24.5
14.3-23.2
39-47.2
29-33
19.5-39
16.9-31.7
6.7-31.6
8.6-10
24.1
13.6-34.2
34.8
24.6-42.3
44.2-49.5
28.7
17.4-23
20.7-28.2
32-34
22.6-34
20-45.5
20.9-32.8
60.5-80.4
47-60
28.5-63.7
22.5-64.3
12.8-42
48.4
47.2
15.2-28
56.3
17.5-66.3
22-54
42.1-66.7
44.2-63.3
30.3-39.8
20.1-39.3
40-54.2
40-44.7
Abbreviations: [>1C] = Double first-cousin marriage; [1C] = First-cousin
marriage.
The CTGA Database
Reporting information on genetic disorders among Arab
people in printed publications is not a practical process
and usually results in rapidly outdated coverage due
to the continuous process of describing more genetic
disorders in the region. To overcome this problem,
Tadmouri and Bissar-Tadmouri (1999) initiated an
early attempt to maintain offline tabular lists of 374
genetic disorders described in Arab individuals, with
corresponding references, by monitoring international
disease databases and scanning bibliographic indices.
The number of maintained records increased to 752
entries early in 2004 (unpublished data). In March 2004,
the name ‘Catalogue of Transmission Genetics in Arabs’
(CTGA) Database was coined for any future online
database that may materialize out of this continuous
survey (Tadmouri, 2004). Later that year, the Centre for
Arab Genomic Studies (CAGS) started implementing
its proposal to launch a pilot CTGA Database by
constructing major software components of the Database
and testing them separately. The CTGA database was
then assembled and tested with limited amounts of data
prior to its public release on the 30th of November 2004
(Tadmouri et al., 2006).
Today, the CTGA Database is defined as a continuously
updated catalogue of bibliographic material and
observations on human gene variants, and inherited,
or heritable, genetic diseases in Arab individuals
(Tadmouri et al., 2006). Its update process is largely
driven by the diverse methods used at the Centre for
Arab Genomic Studies to collect data and information
on genetic conditions in Arab patients including from
various sources that include bibliographic indices,
regional peer-reviewed medical publications, and
personal submissions (Tadmouri, 2008). The size of
the pool of international and national articles surveyed
to collect data for the CTGA Database during the years
2004-2010 mounts to nearly 73,000 articles. From this,
nearly 10,000 articles were investigated in detail during
the surveys to collect data for the UAE, Bahrain, Oman,
and Qatar. Of these, 2,804 articles contained informative
details about the occurrence of genetic disorders in Arab
populations in the region.
Genetic Disorders in Arab Populations
In December 2010, the CTGA Database hosted 955
entries for phenotypes/diseases and 373 entries for
corresponding genes in Arab individuals (see: Appendix
2). These data still reflect a dominance of clinical
observations over molecular analyses in most of the
research conducted in the region (Figure 1.2). Yet,
indications do demonstrate that a slow improvement
in this situation is taking place. For example, the
ratio of gene:disease records in the CTGA Database
increased from 0.36:1, to 0.38:1, and to 0.39:1 for years
2006, 2008, and 2010, respectively (Tadmouri, 2006;
Tadmouri, 2008).
GENETIC DISORDERS IN ARABS
Table 1.1. Consanguinity rates in Arab populations. Minimum
and maximum reported rates are indicated when available
[reviewed in: Tadmouri et al., 2009; include updates for Bahrain
(Al Arrayed, 2006), Morocco (Jaouad et al., 2009), and Qatar
(Sandridge et al., 2010).
Nearly two-third of genetically transmitted diseases in
Arab patients follow an autosomal recessive mode of
inheritance (approximately 61%). High consanguinity
rates and the extended family structure, commonly
present in Arab societies, are likely explanations for
this observation (Tadmouri et al., 2009). Less common
modes of inheritance include autosomal dominant (28%)
and X-linked traits (6%; Figure 1.3).
The Spectrum of Disease and Gene Diversity in Arab
Populations
Diversity of disease groups and affected systems:
Nearly, one-third of the genetic disorders in Arabs
result from congenital malformations and chromosomal
abnormalities (34%) and are followed by endocrine and
metabolic disorders (19%). Major affected systems
include the nervous (11%) and the blood and immune
systems (6%). Neoplasms account for 5% of all disorders
observed in Arabs. Other groups of genetic disorders are
less prevalent in the region (Figure 1.4).
Diversity of disease incidence: Several groups of
genetic disorders have reached epidemic values
and occur at extremely high annual incidences of
> 100 cases/100,000 live births among Arab individuals.
This group encompasses all hemoglobin disorders
(thalassemias, sickle cell disease, and hemoglobin
variants), G6PD deficiency, Down syndrome, cancers
(breast, ovarian, cervical, lung), intestinal carcinoid
GENETIC DISORDERS IN THE ARAB WORLD QATAR
17
1
Figure 1.2. Disease and gene records in Arab countries according to the CTGA Database (December 2010).
Figure 1.3. Classification of genetic disorders in Arabs according to modes of inheritance (December 2010).
Figure 1.4. Classification of genetic disorders in Arabs according to the World Health Organization International
Classification of Disease version 10 (December 2010).
18
GENETIC DISORDERS IN THE ARAB WORLD QATAR
Diversity of disease geography: Genetic disorders are
not equally distributed over the geography of the region.
Almost half (48%) of these disorders occur in a single
Arab country or population such as, the Lebanese type
of mannose 6-phosphate receptor recognition defect
(Alexander et al., 1984), the Bedouin spastic ataxia
syndrome (Mousa et al., 1986), 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 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).
A third of the Arab disorders are limited to two or three
Arab countries (21%, and 12%, respectively). Other
genetic disorders occur in four or more countries (17%).
In this later group, some genetic disorders hint for specific
regional occurrence, such as in the case of LaurenceMoon syndrome in the Arabian Peninsula and autosomal
recessive osteopetrosis type 1 and wrinkly skin syndrome
in the Arabian Peninsula and the Levant (Figure 1.5).
Finally, a number of disorders have a wide geographical
presence encompassing 10 or more Arab countries. This
group includes glucose-6-phosphate dehydrogenase
deficiency, alpha- and beta-thalassemias, insulin- and
noninsulin-dependent diabetes mellitus, hydrocephalus,
familial Mediterranean fever, cystic fibrosis, sickle
cell anemia, hereditary multiple leiomyoma of skin,
anencephaly, and protein S (Figure 1.5).
Diversity of clinical subtypes: Many of the broad groupings
of genetic disorders are further classified into types and
subtypes in Arab patients indicating a heterogreneity in
the features associated with these disorders. For example,
mucopolysaccharidosis occurs in at least five types in
the south of the Arabian Peninsula (IIIA, IIIB, VI, and
VII). In Oman, glycogen storage disease is reported
into four distinct types (I, II, III, and IV) and spinal
muscular atrophy is associated with three types (I, II,
and III). This latter disease also occurs in three variants
in the Bahraini, Saudi, and Kuwaiti populations. In the
UAE population, three variants occur for epidermolysis
bullosa (Junctional Herlitz type, junctional non-Herlitz
type, and junctionalis with pyloric atresia) as well as
osteogenesis imperfecta (I, IIA, and III). Some of the
disorders that occur in other Arab regions with multiple
variants include: Deafness (aminoglycoside-induced,
autosomal dominant nonsyndromic sensorineural 15,
autosomal recessive 9, 12, 13, 14, 16, 21, 22, 27, 30, 31,
32, 33, congenital neurosensory 10, neurosensory 1, and
neurosensory 2, congenital with total albinism, and with
onychodystrophy osteodystrophy and mental retardation
syndrome), Charcot-Marie-Tooth disease (axonal 2B1,
2H, 2K, 4A, 4B2, 4C, and 4H), renal tubular acidosis
(distal autosomal dominant, distal autosomal recessive,
distal with progressive nerve deafness, and distal with
nephrocalcinosis, short stature, mental retardation, and
distinctive facies), spastic paraplegia (autosomal recessive
5A, 5B, 20, 23, and 24, and autosomal dominant 3 and 4),
Ehlers-Danlos syndrome (III, VI, VIB, and the progeroid
form), limb-girdle muscular dystrophy (2A, 2B, 2C,
2D, and 2I), spinocerebellar ataxia (1, 2, 7, autosomal
recessive 2 and 5, and autosomal recessive with axonal
neuropathy), Usher syndrome (ID, IE, IG, IIA, IIB, and
III), Parkinson’s disease (2, 6, 7, and 9), arthrogryposis
(type 1, 2A, multiplex congenital, and multiplex
congenital neurogenic type), cardiomyopathy (dilated
1A, dilated autosomal recessive, familial restrictive 1, and
congestive with hypergonadotropic hypogonadism), and
many others.
GENETIC DISORDERS IN ARABS
tumors, diabetes, obesity, achondroplasia, Alzheimer’s
disease, anencephaly, atrial septal defect, attention deficithyperactivity, Caffey disease, celiac disease, coarctation
of aorta, atopic dermatitis, febrile convulsions, Graves
disease, Hashimoto thyroiditis, benign hematuria,
hemochromatosis, hydrocephalus, hypercalciuria, hypercholesterolemia, essential hypertension, hypospadias,
intussusceptions, myopia, neural tube defects, neutropenia,
orofacial cleft, polycystic kidneys, polyhydramnios,
preeclampsia, infantile hypertrophic pyloric stenosis,
Sjorgen syndrome, strabismus, ischemic stroke, Takayasu
arteritis, Wolff-Parkinson-White syndrome, and others.
Many other disorders do occur in Arab populations at
higher incidence rates when compared to world data, these
include: Tetralogy of Fallot, familial Mediterranean fever,
deafness, Noonan syndrome, Meckel syndrome, and
spondyloarthropathy. The overwhelming distribution of
these diseases in Arabs is best explained by the exposure
of Arab countries to common environmental factors
that encouraged natural selection for these disorders
such as malaria in the case of hemoglobinopathies,
dietary traditions in the case of G6PD deficiency, and
consanguineous marriages in the case of many autosomal
recessive disorders.
Diversity of clinical outcomes due to comorbidity:
Various genetic disorders occurring at epidemic levels
appear in many individuals with an array of other distinct
disorders at a rate higher than expected by chance, thus
the term comorbidity. In fact, many studies reviewed in
the CTGA Database reveal the presence of comorbidity in
patients from the region especially with major disorders
including thalassemias, sickle cell disease, cystic fibrosis,
Down syndrome, G6PD deficiency, and many others
(Table 1.2). In certain cases, the striking occurrences of
such comorbidities motivated scientists to explore the
clinical outcomes such as in the case of Mohammad and
colleagues (1998) who studied the coexistence of sickle
cell disease with G6PD deficiency and found out that
severe G6PD deficiency occur in 47% of individuals with
sickle hemoglobin in Bahrain. In an independent study
of six patients with cystic fibrosis, Khan and Mohammad
(1985) described a reduced G6PD enzyme activity in four
of their patients. A decade later, Al Arrayed and Abdulla
(1996) studied the incidence of cystic fibrosis in Bahrain
retrospectively by reviewing the records of patients
diagnosed with the disorder during a 17-year period
in a major hospital in Bahrain. The survey included a
total of 27 patients, including 25 Bahrainis, with cystic
GENETIC DISORDERS IN THE ARAB WORLD QATAR
19
fibrosis among whom 98% also had G6PD deficiency.
The common presenting clinical picture was failure to
thrive (66%), pneumonia (62%), hypochloremic alkalosis
(44%), and anemia (37%) with a mortality rate of 60%.
1
In a study of patients with cardiomyopathy in Qatar, ElMenyar et al. (2006) noticed an array of rare associations
with familial antiphospholipid syndrome, Ebstein disease,
HbH disease, Crohn’s disease, and thalassemia. In the later
case, comborbidity of cardiomyopathy and thalassemia
was found to have the shortest period between diagnosis
and death (El-Menyar et al., 2006). Certainly, the systemic
study of comorbidity would represent a main approach to
study the clinical complexity in Arab patients with genetic
disorders. Once epidemiologically established through
population or community surveys, the study of the
comorbidity direction and of the chronological patterns
of associated clinical entities may then be translated into
enhanced care of patients, selection of initial treatment,
evaluation of treatment effectiveness, and improvement
of prognosis.
Diversity of novel disorders: Arab scholars and researchers
contributed to the description of many new syndromes
and variants, such as: Najjar syndrome (Najjar et al.,
1973), Barakat syndrome (Barakat et al., 1977), Abdallat
syndrome (Abdallat et al., 1980), Fadhil syndrome (Fadhil
et al., 1983), Woodhouse-Sakati syndrome (Woodhouse
and Sakati, 1983), Al-Awadi-Raas-Rothschild syndrome
(Al-Awadi et al., 1985), Malouf syndrome (Malouf et
al., 1985), the Teebi type of hypertelorism (Teebi, 1987),
Jalili syndrome (Jalili and Smith, 1988), Naguib-RichieriCosta syndrome (Naguib, 1988), Teebi Naguib Al-Awadi
syndrome (Teebi et al., 1988), Majeed syndrome (Majeed
et al., 1989), Teebi Al Saleh Hassoon syndrome (Teebi et
al., 1989), Teebi-Shaltout syndrome (Teebi and Shaltout,
1989), Dudin-Thalji syndrome (Dudin and Thalji, 1991),
Sanjad-Sakati syndrome (Sanjad et al., 1991), Al-Gazali
syndrome (Al Gazali et al., 1994), Temtamy preaxial
brachydactyly syndrome (Temtamy et al., 1998), Al AqeelAl Sewairi syndrome (Al Aqeel et al., 2000), Megarbane
syndrome (Megarbane et al., 2001), El-Shanti syndrome
(El-Shanti et al., 2003), Bosley-Salih-Alorainy syndrome
a.
b.
c.
d.
e.
Figure 1.5. Computer generated maps indicating the relative geographic distribution of (a) Laurence-Moon syndrome, (b) autosomal
recessive osteopetrosis type 1, (c) wrinkly skin syndrome, (d) glucose-6-phosphate dehydrogenase deficiency, and (e) hydrocephalus
in the Arab World according to the CTGA Database (December 2010).
20
GENETIC DISORDERS IN THE ARAB WORLD QATAR
Disease
Comorbidity
Alpha-thalassemia
Wolman disease
Alpha-thalassemia
Cardiomyopathy
Dyskeratosis congenita, X-linked
G6PD deficiency
Pycnodysostosis
Beta-thalassemia
Ehlers-Danlos syndrome type III
G6PD deficiency
Glioblastoma multiforme
Infantile hypertrophic pyloric stenosis 1
Sickle cell disease
Sickle/beta-thalassemia
Absence of abdominal muscles with urinary tract
abnormality and cryptorchidism
Choanal atresia, posterior
Moyamoya syndrome
Tetralogy of Fallot
Dyskeratosis congenita, X-linked
Pycnodysostosis
Alpha-thalassemia
Beta-thalassemia
Blepharophimosis, ptosis, and epicanthus inversus
G6PD deficiency
Hand-foot syndrome
Chromosome 18p deletion syndrome
Down syndrome
Frontonasal dysplasia
Holt-Oram syndrome
Crohn’s disease
Ebstein disease
Familial antiphospholipid syndrome
HbH disease
Beta-thalassemia
Cystic fibrosis
Down syndrome
G6PD deficiency
Sickle cell disease
Tetralogy of Fallot
Cardiomyopathy
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 greater (Hall et al.,
1978) and these patients often must travel significant
distances to get specialized treatment (Carnevale et al.,
1985).
In recent years, heath economists have made significant
advances in calculating the costs of genetic disorders,
as well as disabilities caused by various congenital
abnormalities. There are now generally-accepted annual
‘cost of illness’ estimates per patient for all common
genetic conditions including: Down syndrome (US$
36,000; Boulet et al., 2008), cystic fibrosis (US$ 28,000;
Eidt et al., 2009), Niemann-Pick disease type C (US$
27,000; Imrie et al., 2009), inherited leukodystrophy
(US$ 22,579; Bonkowsky et al., 2010), sickle cell disease
(US$ 16,668; Kauf et al., 2009), beta-thalassemia (US$
7,000; Karnon et al., 1999), diabetes mellitus (US$ 1,500;
Wang et al., 2009), asthma (US$ 1250; Bahadori et al.,
2009), retinal dystrophy (US$ 1,000; Porz et al., 2010),
hemophilia (US$ 1000; Meyers et al., 1972), and atopic
dermatitis (US$ 1000; Fowler et al., 2007). Overall, the
total annual cost of the most common 20 genetic ailments
in the Arab World is estimated not to be less than $13
billion per year (reviewed in Tadmouri, 2008).
GENETIC DISORDERS IN ARABS
Table 1.2. Selected examples of genetic disease comorbidities
recorded in the CTGA Database (September 2010).
Preventive Aspects of Genetic Disorders in Arabs
(Tischfield et al., 2005), and Megarbane-Jalkh syndrome
(Megarbane et al., 2008).
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, several disorders, including chromosomal
(Down syndrome, Turner syndrome), single-gene (sickle
cell disease, thalassemia, G6PD deficiency, hemophilia,
inborn errors of metabolism) 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 economic
impact of each of these disorders differs according to
their severity, many of which involve medical, surgical,
or cosmetic interventions. Generally, these conditions
are a leading cause of spontaneous abortion, neonatal
death, and increased morbidity and mortality in both
children and adults. They are a significant health care
and psychosocial burden for the patient, the family, the
health care system and the community as a whole (ElHazmi, 1999).
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).
Prevention programs are effective in decreasing the
impact of genetic disorders on families and societies and
also lead to early treatment and improvements in outcome
and prognosis (Al-Odaib et al., 2003). A detailed analysis
of the molecular basis of defined genetic diseases
indicates that approximately half of the genetic disorders
described in Arabs (56%) result from single-gene or gene
loci alterations (Figure 1.6). Hence, in the presence of
available expertise and resources preventive programs
may be successfully applied in many Arab communities
especially in the areas of newborn screening and carrier
screening for prevalent genetic disorders. Yet, having the
technology and resources alone are not enough. To start
an effective program it has to be orchestrated by different
strata of the society including patient representatives,
medical geneticists, physicians, public health physicians,
sociologists, ethicists, pharmaceutical industries, policy
commentators, and policy makers within governments.
Moreover, distinct policy areas have to be defined when
dealing with a prevention program for genetic disorders,
these include:
The science base: through which disease conditions
could be defined according to their attributed burden,
GENETIC DISORDERS IN THE ARAB WORLD QATAR
21
prevalence of the genetic trait, and natural history in the
target population from susceptibility, to latent, and to
overt disease. Experts have to also evaluate the safety
and effectiveness of possible tests involved. Most
important, population screening should be performed
only if the abnormal finding in question can change the
clinical management, and that this management will
improve the prognosis.
Educational strategies: should be built based on
the concept of “genetic literacy”. This could be best
achieved by applying interactive processes of dialogue
and discussion in educational processes. For this, new
biology has to be integrated as a necessary component of
general education as well as in the education and training
of all health professionals. In this framework, medical
geneticists, genetic counselors, and clinical psychologists
have a crucial role in making the prevention program
acceptable by the target population by clear explanation
of associated risks, proper parental consenting, and
counseling (Khalifa, 1999; Fadel, 2008).
1
Regulatory framework: has to be directed to resolve the
widespread misunderstanding about genetics, especially
the concept of genetic risk for a disease. In this area,
scientists and the media have a great role. Politicians
also have a responsibility in leading the public debate and
making available adequate infrastructures, surveillance
policies, and supportive financing mechanisms.
Cultural sensitivity: is a required safeguard to protect
the public from premature and inappropriate use of
genetic information, stigmatization, and discrimination,
and to avoid coercion or manipulation (Meyer, 2005).
Financial framework: is a vital factor in securing the
continuity of a preventive program. In most cases, the
annual cost of a nationwide disease prevention program
would not exceed the cost of treating one annual birth
cohort of patients with a genetic condition for one year
(WHO, 1996).
Genetic Disorders Prevention Programs in Arab
States
Several Arab States have initiated systematic cost
effective prevention programs for certain common
genetic conditions using a variety of approaches:
Neonatal screening: This involves the establishment
of national or hospital based registries for congenital
abnormalities (e.g., Oman and the UAE) and the
implementation of biochemical technologies to depict
the incidence of many inherited disorders. Currently,
Bahrain, Egypt, Lebanon, Oman, Palestine, Qatar,
Saudi Arabia, and the UAE execute national and private
newborn screening programs varying from one disease to
23. Pilot newborn screening programs are implemented
in Jordan, Kuwait, and Tunisia. With an estimated 10
million newborns per year, a wide coverage of such
22
GENETIC DISORDERS IN THE ARAB WORLD QATAR
Figure 1.6. Distribution of genetic disorders in Arabs according
to the number of causative gene loci (December 2010).
programs in the Arab World becomes an important
challenge (reviewed in Saadallah and Rashed, 2007;
Krotoski et al., 2009).
Family screening: In Arab countries this proves to be
more effective than a population screening program
due to the high level of consanguinity and the relative
clustering of genetic diseases in specific population
groups (Defesche et al., 2004).
Premarital screening: Several Arab countries have
introduced premarital screening, especially for
hemoglobin disorders as in Bahrain (Al Arrayed, 2005),
Jordan (Hamamy et al., 2007), Lebanon (Inati et al.,
2006), Palestine (Tarazi et al., 2010), Saudi Arabia
(Al-Suliman, 2006; Alhamdan et al., 2007), Tunisia
(Chaabouni-Bouhamed, 2008), and the UAE (Al-Gazali
et al., 2005).
Prenatal diagnosis: Is an important component that
requires an extensive social framework and without
which a prevention program is practically gagged. In
most Arab countries, except Tunisia, selective termination
of pregnancy is not legally available (ChaabouniBouhamed, 2008). Yet, limited applications of prenatal
diagnosis were also reported from Egypt (Elgawhary et
al., 2008), Lebanon (Eldahdah et al., 2007), and Palestine
(Ayesh et al., 2005).
Preimplantation genetic diagnosis: This is a more
welcomed approach since it allows the avoidance of
selective pregnancy termination. Successful applications
of this approach have been reported in Jordan (Kilani
and Haj Hassan, 2002; Abdelhadi et al., 2003) and
Saudi Arabia (Ozand et al., 2005; Hellani et al., 2009;
Alsulaiman et al., 2010). A recent study from the UAE
found that most people favor this mode of prevention (AlGazali, 2005).
Arab families are highly close-knit units, integrated within
the mesh of the larger culture-bound socioeconomic
network. Families form the centre of the Arabian society
and religion as an integral part of the culture. The major
involvement of the family and society on genetic disorders
in the Arab World does not come, thus, as a surprise. The
most important ways in which the society plays its role in
the manifestation of genetic diseases includes, but is not
necessarily restricted to, the perception of family history
and compliance to medical and genetic advice.
Family history: Close to 115 diseases catalogued in the
CTGA Database document a positive family history of
corresponding conditions. Interestingly, within this group,
a large number of records document consanguinity within
the family. This could again be due to the high prevalence
of consanguinity in the region, an assumption highly
supported by the autosomal recessive mode of inheritance
of most of these disorders. In such a scenario, traditional
genetic counseling cannot be expected to be as successful
as reported in other societies with lower rates of inbreeding
and less emphasis on families. Instead, genetic counseling
in the Arab society needs to be oriented towards families.
Such family oriented counseling can have an enormous
impact on multiply consanguineous kindred where rare
genetic disorders are clustered (Al-Gazali et al., 2006).
Unfortunately, the medical community in the Arab region
demonstrates a very high turnover rate. This is especially
true for the Gulf States where expatriates form the major
mass of the medical community. As a result, there is a
dearth of family physicians who have been involved with
families for a fairly long enough time to know the genetic
background of the entire family. In Western societies,
family physicians routinely use their experience with the
history of the family right from prenatal and newborn
screening to the early recognition of individuals at risk of
disease (Feder and Modell, 1998). Since such a system
is lacking in the region, specialists may find it difficult
to diagnose a genetic disorder from consultation with the
patient in isolation.
Non-compliance: Therapeutic non-compliance is a feature
frequently encountered by physicians. This phenomenon
is characterized by a refusal of the patient to abide by the
recommendations of the health care provider. Apart from
the direct effect on the treatment outcome of the patient,
non-compliance can also cause an indirect increase in the
financial burden on the society by way of excess urgent
care visits, hospitalizations and higher treatment costs (Jin
et al., 2008). It has been seen that chronic diseases tend
to lead to lower rates of compliance than do diseases of a
short duration (Farmer et al., 1994; Gascon et al., 2004).
Genetic diseases tend to require life-long treatment, and
thus patients are highly susceptible to resorting to noncompliance with the treatment strategies. The CTGA
Database documents 17 cases of non-compliance within
the patient population of the four GCC countries studied
in detail. Data on this subject may not be complete since
most authors do not deem it necessary to concentrate on
this seemingly non-vital aspect. CTGA Database records
clearly demonstrate that non-compliance can occur in any
of the phases of management of the genetic screening.
Thus, there are instances of parents at-risk of having an
affected child refusing to get themselves screened (Joshi
et al., 2002) and of parents not complying with treatment
options for their children (Al Ansari, 1984; Soliman et
al., 1995). More dangerous is the practice of not only
disregarding the medical advice, but also seeking the
help of traditional ‘healers’, often leading to disastrous
consequences (Ahmed and Farroqui, 2000). In most
cases of non-compliance by parents, however, parents
tend to get back to the physician and restart treatment
once the symptoms in the children begin to worsen, and
they see that there is no option left. Patient refusal, on
the other hand, is more disturbing, since those patients
who demonstrate non-compliance on their own do not
generally restart treatment later, even with adequate
counseling (Khandekar et al., 2005). Patients may show
non-compliance by refusing invasive diagnostic methods
(Bhat and Hamdi, 2005), discontinuing medication
(Khandekar et al., 2005), refusing surgery (Venugopalan
et al., 1997), or refusing a medically advised termination
of pregnancy (Gowri and Jain, 2005).
GENETIC DISORDERS IN ARABS
Arab Family Perception of Genetic Disorders
Genetic literacy: A characteristic feature of the Arab
society is the extremely low level of genetic literacy,
which makes the role of the genetic counselor quite
difficult. Instances of successful applications of genetic
counseling in affected families, which have helped in the
early diagnoses and management of disease conditions,
can be extracted from the CTGA Database (Subramanyan
and Venugopalan, 2002). However, generally, people
in these populations are reluctant to refer to a genetic
counselor under the erroneous assumption that counselors
would advise them on personal issues, such as the choice
of a marriage partner or on their reproductive options.
Unfortunately, such misconceptions exist not only among
the patients themselves, but also among the health care
providers (Hamamy and Bittles, 2009).
Education: A direct correlation has been demonstrated
between the level of education and awareness and early
detection and better management of genetic disorders in
Arab populations (Al-Mahroos, 1998; Al-Saweer et al.,
2003; Al-Moosa et al., 2006). Of note is the observation
that compulsory premarital screening for identifying
thalassemia carriers increased public awareness on
genetic diseases in general, with requests for counseling
on other conditions increasing (Hamamy and Bittles,
2009). It may also be a useful strategy to integrate
genetic counseling into the procedure of routine prenatal
care, so that it may be better accepted by the population.
Concluding Remarks
At present, congenital malformations are the second
leading cause of infant mortality in countries of the
Gulf Cooperation Council, including Bahrain, Kuwait,
Oman, and Qatar. Reports from Saudi Arabia indicate
GENETIC DISORDERS IN THE ARAB WORLD QATAR
23
that congenital malformations account for about 30% of
perinatal deaths (Hamamy and Alwan, 1994). Additionally,
in most Arab populations the birth prevalence of severe
recessively inherited disorders may approach that of
congenital malformations (Alwan and Modell, 1997).
1
Approximately 27% of reported genetic disorders in
Arabs remain confined to clinical observations with no
significant attempts to depict their molecular pathologies.
A large number of these disorders are confined to local
families and communities and have not been described
elsewhere. Mummifying these disorders at the clinical
level represents a very serious loss for the global scientific
community, since permanently burying information
regarding hundreds or thousands of human gene variants
might lead to the loss of important information that can
be used for research, and potential cures for genetically
transmitted conditions (Editorial, 2006). Unfortunately,
no established system is yet available in many Arab medical
research institutions to translate clinical observations
into genetic data. The limited examples available in
the Arab World are usually local efforts mostly exerted
by medical practitioners and clinical geneticists who
have developed a particular interest or have specialized
in molecular studies (Naveed et al., 2006; Naveed et
al., 2007). Increasing the emphasis on subjects such as
molecular genetics in medical schools in the region will
help to create future generations of physicians and other
medical personnel capable of establishing the phenotype/
genotype correlations that are key elements in the modern
medical applications of genetics.
Databasing prevalence data as well as the molecular
pathologies leading to genetic disorders in Arabs offers a
solid groundwork to promote proper education in the field
and employ knowledge-driven development to address
urgent regional health needs. The organization of such
information also promotes Arab scientists to a position of
strength and allows them to contribute to global research
efforts in the field and build sustainable research activities
based upon education and the improvement of human
health.
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