Chapter 1

Introduction: Genetic Diversity Among Arabs

Ahmad S. Teebi

There is perhaps no region with a richer history or a more diverse ethnic, cultural

and religious makeup than the Arab world. It is the cradle of civilization and

birthplace of the world’s three major monotheistic religions. Despite their hetero-

geneity, the Arab countries are united by their common language and location in the

largest arid zone of the world: the Sahara and African deserts and their contiguous

semi-arid lands. The geographical area of the Arab world covers about 14 million

km2 and spans two continents, covering a distance of 6,375 km from Rabat on the

Atlantic to Muscat on the Arabian (Persian) Gulf (Bolbol and Fatheldin 2005)

(Fig. 1.1). Consequently, the Arab populations, currently exceeding 300 million,

representing 5% of the world populations, are mainly concentrated in the relatively

fertile regions, particularly along the Nile River, in the valleys of the Euphrates and

the Tigris, and along the coastal area of North Africa, Syria, Lebanon and Palestine/

Israel. These four regions account for 84% of the Arab populations and only 54% of

their income. The GCC countries (Gulf Co-operation Council), comprising Saudi

Arabia, Kuwait, United Arab Emirates, Qatar, Bahrain and Oman, have about 45%

of the income but only 10% of the Arab populations (Grissa 1994). With two thirds

of the Arab countries producing oil, there is little doubt that it is the single most

important factor in the region’s economic development (Raffer 2007).

Past and Present

The history of the Arabs extends back more than 5,000 years. Around 3500 BC,

Semitic-speaking people of Arabian origin migrated into the valley of the Tigris and

Euphrates rivers in Mesopotamia, eventually becoming the Assyro-Babylonians.

A.S. Teebi

Weill Cornell Medical College, Qatar Foundation, Doha, Qatar

e-mail: ast2003@qatar-med.cornell.edu

A.S. Teebi (ed.), Genetic Disorders Among Arab Populations,DOI 10.1007/978-3-642-05080-0_1, # Springer-Verlag Berlin Heidelberg 2010

3

Another group of Semites left the Arabian Peninsula about 2500 BC and settled

along the eastern shore of the Mediterranean; some of these migrants became the

Amorites and Canaanites of later times (Bram and Dickey 1993). Beginning from

the seventh century, Arabs, proclaiming the new religion of Islam, ventured from the

Arabian Peninsula and conquered the wide area from the Arabian/Persian Gulf to the

Atlantic ocean. The Arab civilization soon became the world’s most prominent, and

Arab and Islamic science and medicine flourished. Islamic medicine was based on

Greek medicine and also on Quranic teachings and the model set by the prophet

Mohammad in the Hadith. Islamic medical scholars and centers flourished and

several authors, including Al-Ruhawi and Al-Tabari, wrote on Islamic medicine

and medical ethics (Rispler-Chaim 1993).

During the past few decades, good but inconsistent economic progress has been

made by the Arab countries of the Middle East and North Africa. In the same

period, most Arab countries have maintained high total fertility rates. Only recently

have these rates declined, and only in a few Arab countries, notably Bahrain, Egypt,

Tunisia and Lebanon (Faour 1989). Infant mortality has fallen by more than half

and life expectancy has increased from 48 to 67 years. High inbreeding continues to

prevail in most Arab countries. Education levels have improved: primary school

enrollment is nearly 100%, secondary school enrollment has tripled and female

enrolment has increased fivefold (World Bank 1994).

Language is what unites the Arabs. Formal Arabic is the official language in all

the 22 countries of the Arab League. The overwhelming majority of Arabs (over

90%) are Muslim, and predominantly Sunni. In some countries such as Iraq,

Fig. 1.1 Map of the Arab world

4 A.S. Teebi

Lebanon and Bahrain, Shi’ite Muslims exist in proportions similar to or slightly

higher than Sunnis. A number of Arab countries contain sizeable Christian com-

munities; in Lebanon, for example, 43% of the population is Christian (Husseini

1994).

On the health front, the region, while undergoing tremendous transformations

(reduced mortality rates, the eradication of several epidemics and the improved

overall health conditions) still suffers from an increased incidence of nutritional

problems, malaria and tuberculosis, in addition to the rise in importance of health

problems that are related to modern lifestyles – smoking, stress, heart disease,

diabetes mellitus and genetic disorders. Furthermore, the interplay of culture,

economics, natural endowments and man-made pollution activities results in health

problems, some of which are genetically related.

Ethnic Diversity

Despite its linguistic, religious and cultural cohesion, the Arab world is also rich in

diversity. In addition to Muslim and Christian Arabs, the area is home to Kurds,

Druze, Berber, Armenians, Circassians, Jews and other minorities. The Arabs

themselves, in most parts of the Arab world, are the result of admixture with

other populations in the area, through migration to or from other parts of the

world, or across the borders (such as Persians, Turks, South-East Asians, Europeans

and Africans). Wars throughout history, particularly the Crusades, have contributed

to this unique mosaicism. Other than this mosaic of genetically heterogeneous

populations, relatively homogeneous populations or isolates exist. These include

some Bedouin tribes, Nubians and Druze among others.

The Arab/Muslim Family

Among Arabs, descent is reckoned through males rather than females. Married men

and their wives live with their father in one large household (or at least very close to

him) whenever possible, and marriages with relatives are favored. Although polyg-

amy is allowed in Islam, it is practiced only on a narrow scale and mainly with the

aim of producing more children. In some societies, such as in Tunisia, polygamy is

strictly controlled. Broadly speaking, the Arab man or woman values being related

to a large tribe or extended kindred. He or she can often trace back his or her origin

through several generations. Many tribes, in GCC countries for instance, keep

family trees that contain information going back ten or more generations. The

number of children per family is large, averaging more than four. The average

family size that includes the parents (from 1987 to 1993) varied between five in

Egypt and eight in Kuwait.

1 Introduction: Genetic Diversity Among Arabs 5

Religion, Culture and Genetic Issues

The Arab family, Muslim or Christian, typically has strong faith in God. Muslims

believe the occurrence of disease to be God’s will, as explained in the Quran(Surah 57, pp. 22–23), “No misfortune can happen on earth or in your souls butit is recorded in a decree before We bring it into existence” (Ali 1991). Such belief

helps parents to alleviate feelings of guilt by relating the reason for the child’s

problem to God’s purposeful, non-questionable action, rather than to a “blind

probabilistic event” (Panter-Brick 1992). In Arab countries, prenatal diagnosis is

acceptable for purposes of reassurance or therapy. Termination of pregnancy,

however, at any stage is absolutely forbidden (Haram), unless the mother’s life is

endangered (Hathout 1972). Under Islamic law, according to some interpretations,

termination of pregnancy is considered a crime (Shaltout 1959). However, couples

may avoid pregnancy if they are at an unacceptably high risk of having a child with

a certain genetic defect. On the other hand, while artificial insemination using the

husband’s sperm (AIH) and in vitro fertilization using the husband’s sperm are

acceptable (Mubah), using donor sperm is absolutely forbidden. In general, assisted

reproduction using the husband’s and wife’s gametes is acceptable. Adoption has

been practised since the early ages of Islam. However, “legal adoption” is not

permitted (For details see Al-Aqeel 2007).

Consanguineous Marriage and Endogamy

Consanguineous marriage is common in most Arab populations and is not necessarily

limited to geographic or religious isolates or ethnic minorities. Unlike its largely

taboo status inWestern countries, the practice is deeply rooted in the Arab culture and

has been over many generations. The rates are generally high. They range between

25% in Beirut (Khlat and Khudr 1984) up to 60% in Saudi Arabia and 90% in some

Bedouin communities in Kuwait and Saudi Arabia (Al-Roshoud and Farid 1991;

Panter-Brick 1992). An average figure of about 40% appears to be true in most Arab

countries. The most common form of intermarriage is between first cousins, particu-

larly paternal first cousins and includes double first-cousin marriage. Uncle/niece,

aunt/nephew marriages are forbidden by Quran and are in fact non-existent (Teebi

and Marafie 1988). Consanguineous marriage is more common among Muslims than

among Christians, though it is strictly a cultural feature and not a religious prescrip-

tion. In fact, and according to some religious scholars, Islam discourages consan-

guineous marriages, though it does not forbid it. Inbreeding is more common in rural

areas than in urban regions, although it does not seem to correlate with the economic

status. However, in some rich families and tribes, consanguineous marriages prevail

because of the attachment of people to their families or villages and to keep the

property within the family or tribe. One of the reasons favoring cousin marriage can

be extrapolated from the common Arabic saying “a spouse that you know is better

6 A.S. Teebi

than the one you don’t know, and a cousin takes better care of you” (Panter-Brick

1992). Another contributing factor is the popular belief that consanguineous marriage

offers a major advantage in terms of compatibility of the bride and her husband’s

family, particularly her mother-in-law (Jaber et al. 1994).

Some studies have reported a secular decline in consanguineous marriage, for

example, in Kuwait (Radovanovic et al. 1999), Saudi Arabia (Al-Abdulkareem and

Ballal 1998), Jordan (Hamamy et al. 2005), and Israeli Arab and Palestinians (Jaber

et al. 2000; Zlotogora et al. 2002; Sharkia et al. 2008; Assaf and Khawaja 2009). By

comparison, in the UAE (Al-Gazali et al. 1997), Yemen (Jurdi and Saxena 2003)

and Qatar (Bener and Alali 2006), the overall levels of consanguineous marriage,

including first-cousin unions, have actually increased. This suggests that future

trends may depend on the local political, economic and social factors. Similar to

most Arab populations, the consanguinity rate among the semi-isolated Druze

community in Israel is 49% (Freundlich and Hino 1984). On the other hand, as an

exception, marriages within the clan are forbidden among the Nubian people

(Bayoumi and Saha 1987), and consanguinity studies among four tribes living in

western Sudan found no incidence of consanguineous marriages among the indige-

nous people living within the Nuba mountains. However, this may not be exactly

the case of the Egyptian Nubian people of Kom Ombo.

Autosomal Recessive Disorders

When a rare autosomal recessive mutation is present in a family, the chance that a

disease will manifest in this family increases if a consanguineous marriage occurs

and when the number of children is large. Such conditions are optimal in the Arab

world, where previous observations demonstrated an increase in the frequencies of

autosomal recessive conditions (Teebi 1994; Hamamy and Alwan 1994; Teebi and

Teebi 2005; Al-Gazali et al. 2006). Autosomal recessive disorders among Arabs

have a characteristic pattern that will be subsequently discussed according to their

conspicuous features.

Hemoglobinopathies

Hemoglobinopathies constitute a major health problem in Arab countries. The

genes for sickle cell hemoglobin (HbS) and a and b thalassemias are found in all

Arab countries with different frequencies in different Arab countries and even

within different regions within the same country, as is the case in Saudi Arabia.

The sickle cell trait frequency ranges from less than 1% along the Nile in Egypt to

20% or more in Siwa oasis in Egypt, Bahrain and some parts of Saudi Arabia.

Generally, HbC is very rare except in Morocco, where it is twice as common as

HbS. A number of new Hb variants have been reported also, including HbO-Arab,

1 Introduction: Genetic Diversity Among Arabs 7

HbJ-Cairo, Hb-Riyadh and Hb-Khartoum among others. Hb S/O-Arab is a severe

sickling hemoglobinopathy similar to homozygous sickle cell anemia; however, it

is rarely found (Zimmerman et al. 1999).

Molecular studies of HbS indicate that an independent mutation (Arab-Indian or

Saudi-Indian haplotype) occurred in eastern Saudi Arabia and the Indian subconti-

nent region and spread from there to other parts of the Arab world, while in the

western region of Saudi Arabia and North African countries, the gene may have

been transported from Benin and Senegal in Africa (Benin and Senegal haplotypes).

No specific ß thalassemia mutations are confined to Arabs and the Mediterranean

and Asian mutations are encountered at variable frequencies. a thalassemias,

however, generally result from a gene deletions.

FMF and Other Auto-inflammatory Disorders

Familial Mediterranean fever (FMF), also known as paroxysmal polyserositis, is an

important clinical and public health problem in a number of Arab countries. It is

very common in Lebanon, Jordan and among Palestinians. The frequency among

Palestinians and Jordanians was estimated to be at least 1 in 2,000, a figure similar

to that of Armenians and Sephardic Jews (Barakat et al. 1986; Majeed and Barakat

1989). FMF is present also in Iraq, Syria, Kuwait, Egypt and Saudi Arabia. In a

number of situations, the diagnosis is missed and the chronic nature of the problem

taxes the medical care facilities. Patients with amyloidosis as a complication of

FMF form a large proportion of the load of dialysis and kidney transplantation in a

number of Arab countries. FMF is caused by mutations in MEFV gene on chromo-

some 16 (Pras et al. 1992). The most frequent MEFV mutations found among the

Arabs from Jordan, Palestine, Syria, Iraq, and Egypt, according to their magnitude

of frequency, are M694V, V726A, 694I, and M680I (Majeed et al. 2005; El-Shanti

et al. 2006). The most common mutations among patients from the Maghreb are

M694V and M694I (Belmahi et al. 2006). A744S mutation seems specific to Arab

pouulations and R761H is frequently found in the Lebanese (Medlej-Hashem et al.

2004). There seems to be distinctive clinical picture in Arab patients with FMF

(El-Shanti et al. 2006).

Other auto-inflammatory disorders including Majeed syndrome are discussed

elsewhere in the book.

Muscular Dystrophies and Myopathies

The magnitude of disease entity is apparently large, mostly due to autosomal

recessive conditions. In two surveys, one in the eastern part of Saudi Arabia

(Al-Rajeh et al. 1993) and the other in Kelbia in Tunisia (Romdhane et al. 1993),

the prevalence rate of anterior horn cell diseases, including Werdnig-Hoffmann

8 A.S. Teebi

disease, was 133 and 177 per million respectively compared to 12 per million from

the World Survey (Emery 1991). Similar high incidence was observed in the

Egyptian Karaite community in Israel (Fried and Mundel 1977). In a Libyan

study, the estimated overall frequency of muscular dystrophies was 132 per million

(Radhakrishnan et al. 1987). On the other hand, in the Saudi study, the frequency of

Duchenne muscular dystrophy and myotonic dystrophy was 44 and 88 per million

compared to the same World Survey of 32 and 50 per million respectively. The

figures do not appear to be remarkably different in the two surveys.

A severe childhood autosomal recessive muscular dystrophy (SCARMD) resem-

bling Duchenne muscular dystrophy was first noted in several families from Sudan

and Tunisia. Subsequently, the disease was found to be prevalent in other Maghreb

countries and in the Arabian Peninsula. Recent data comparing Tunisian and

Algerian patients with patients from Morocco indicate genetic homogeneity of

disease in the Maghreb countries (El-Kerch et al. 1994) In a study from Tunisia,

the frequency of this form of muscular dystrophy was found to be equivalent to that

of Duchenne muscular dystrophy (Ben Hamida and Marrakchi (1980). Meanwhile,

in Kuwait the proportion of families with this autosomal recessive disease was

found to constitute at least 36.3% of all ascertained Duchenne or Duchenne-like

muscular dystrophies (Farag and Teebi 1990) compared to 5% in North America

and United Kingdom (Emery 1987). Because this disease is characteristically

highly prevalent among Arabs, it is considered, however, an example of Arab

diseases (Table 1.1). Details of molecular bases of SCARMD are found elsewhere

in this book. Other relatively common disorders include SCARMD-like disorders,

Duchenne and Becker muscular dystrophy, congenital muscular dystrophy, con-

genital myopathies, mitochondrial myopathies and Schwartz-Jampel syndrome.

The latter seems to be more common in the United Arab Emirates.

New Genetic Syndromes First Reported Among Arabs

In the last three decades, the area of new genetic syndromes among Arabs became a

hot point of research and publications. Reports describing new syndromes and

variants came from countries with established genetic services such as in Israel,

Lebanon, Kuwait, UAE, Oman, Egypt, Qatar and Saudi Arabia. In this book, an

exhaustive list of all such syndromes has been compiled. However, it remains

inclusive of very early reports, reports that do not mention the origin of the patient

(s) or reports published in unindexed periodicals. The list contains 160 syndromes,

compared to 113 syndromes in the first edition of this book, published in 1997. Of

these, 133 syndromes are autosomal recessive, 27 are autosomal dominant and five

are possible X-linked, autosomal recessive or mitochondrial disorders. Many other

“newly” characterized disorders were not included in the recent review, either

because they are awaiting further characterization or because of some overlap

with previously known disorders requiring molecular etiologic characterization.

Despite the fact that most Arab populations are still poorly studied genetically, the

1 Introduction: Genetic Diversity Among Arabs 9

number of autosomal recessive syndromes characterized so far appears relatively

large for a group constituting no more than 5% of the world populations. More than

half of the new autosomal recessive disorders were described among people from

Jordan, Palestine and Lebanon, who collectively constitute less than 5% of the Arab

populations. This may reflect the genetic diversity of the Palestinians or Jordanians

and Lebanese as a result of their admixture over time with many populations,

including Arabs, Turks, Kurds, Europeans and Jews, among others. The apparent

clustering of new syndromes and other rare genetic disorders among the Palestinians

and Lebanese may also be an indication that they have access to genetic services that

are not yet available in many other parts of the Arab world. Seven major groups of

syndromes are noted among the newly described syndromes among Arabs. They

include Neurological/neuromuscular/muscular, Dysmorphic syndromes, Ophthal-

mological and Hearing disorders, Bone dysplasia and Skeletal disorders, Dermato-

logical and Fertility syndromes and Inborn Errors of Metabolism.

Many of the newly described syndromes were thought to be “private”, or limited

to single families. Subsequent reports negated the concept of privacy in syndromes.

One of those syndromes was the Nablus mask-like facial syndrome. An autosomal

Table 1.1 Arab genetic diseases: autosomal recessive disorders that are characteristically highly

prevalent among Arabs

Disease MIM # Estimated frequency/

livebirths

References

Bardet-Biedl syndrome 209900 1–2/13,000 Farag and Teebi (1988a,

Farag and Teebi 1989a)

Congenital chloride

diarrhea

214700 1/5,500–13,000

(Arabian

Peninsula)

Kagalwalla (1994),

Badawi et al. (1998)

Congenital

hypoparathyroidism,

seizure, growth

failure, dysmorphic

features

241410 Unknown; most

reported patients

are from Arabian

Peninsula

Sanjad et al. (1991),

Marsden et al. (1994),

Naguib et al. (2009)

Meckel syndrome

Familial Mediterranean

fever

249000

249100

1/3,500

1-1500-2000

Palestinians and

Jordanians

Teebi et al. (1992),

Majeed and Barakat (1989),

El-Shanti et al. (2006)

Werdnig-Hoffmann

disease

253300 1/1,000–1,500 Al-Rajeh et al. (1993), Romdhane

et al. (1993)

Severe childhood

autosomal recessive

muscular

dystrophy

(SCARMD)

253700 1/3,500 (approximate) Ben Hamida and Marrakchi

(1980), Farag and Teebi

(1990)

Nesidioblastosis of

pancreas

256450 1/2,675 (Saudi Arabia) Mathew et al. (1988),

Cherian and Abduljabbar

(2005), Karawagh et al. 2008)

Osteopetrosis with renal

tubular acidosis

259730 Unknown; 70% of all

reported patients

are Arabs

Ohlsson et al. (1986), Fathallah

et al. (1994)

10 A.S. Teebi

recessive example is the Limb/pelvis-hypoplasia/aplasia syndrome described first

in a Palestinian from Kuwait (Al-Awadi et al. 1985). Subsequently, reports also

came from Brazil, Saudi Arabia, Egypt, Israel, Italy and again from Kuwait in a

Bedouin family. Recently the causative gene was elucidated (Woods et al. 2006).

The other example was a new hypogonadism syndrome reported in a Jordanian

family from Kuwait, later seen in a Lebanese family, and recently reported in two

sisters of consanguineous parents from Turkey (Tatar et al. 2009). One of the newly

described syndromes was initially described in five siblings of a Bedouin family in

Kuwait (Teebi et al. 1988). The same syndrome was found in several sibships of the

same tribe, an example of the founder effect (Teebi and Al-Awadi 1991). Several

examples of autosomal recessive disorders relatively common in Qatar, but rare

elsewhere, were recently documented (See Qatar Chapter in this book). They repre-

sent classical examples of founder effect. Table 1.2 provides examples of disorders

with definite tribal occurrence or restricted to large kindred or isolates.

Inborn Errors of Metabolism

Data on metabolic diseases among Arabs are becoming available due to the

introduction of diagnostic facilities and nationwide neonatal screening in several

Table 1.2 Examples of genetic disorders reported to have definite tribal occurrence or limited to

extended kindreds or isolates

Disorder MIM # Community References

Arthrogryposis multiplex

congenita, neurogenic type

208100 Palestinian Jaber et al. (1995)

Bardet-Biedl syndrome 209900 Bedouin in Israel Kwitek-Black et al. (1993)

Cerebrotendinous

xanthomatosis

213700 Druze in Israel Leitersdorf et al. (1994)

Cystic fibrosis

Deafness, Autosomal recessive

219600

220290

Bedouin tribe in Qatar

Northern Tunisia

Abdul Wahab et al. (2001),

Ben Arab et al. (2004)

Homocystinuria 236200 Bedouin tribe in Qatar El-Said et al. (2006)

Hypophosphatemic rickets and

hypercalcuiria

241530 Bedouin tribe in Israel Tieder et al. (1987)

Metachromatic leucodystrophy 250100 Palestinian Zlotogora et al. (1994a),

Heinisch et al. (1995)

Krabbe disease 255200 Palestinian; Druze in

Israel

Zlotogora et al. (1991),

Oehlman et al. (1993)

Pseudohermaphroditism

(male)-17-b-Ketosteroiddehydrogenase def.

264300 Palestinian in

Gaza strip

Rosler (2006)

GM2 gangliosidosis, Sandhoff

variant

268800 Bedouin in

Saudi Arabia

Ozand et al. (1990a, 1992)

Glanzmann thromboasthenia 273800 Palestinian Rosenberg et al. (2005)

Usher syndrome type I 276900 Samaritans in Nablus Bonne-Tamir et al. (1994)

1 Introduction: Genetic Diversity Among Arabs 11

Arab countries (Saadallah and Rashed 2007). However, such data are almost non-

existent from several other countries in the Arab world.

Classic Phenylketonuria and Other Hyperphenylalaninemia

In Egypt, Phenylketonuria (PKU) patients constituted 2.3% of the mentally

retarded (Temtamy et al. 1991). In Kuwait, PKU was found to have a frequency

between 1.6% and 1.86% among institutionalized mentally retarded patients. Six

inmates with PKU belonged to three sibships in a large Kuwaiti kindred originating

in Iran. At least 20 other patients were ascertained at the genetic clinics or

elsewhere (Teebi 1994). A Bedouin family was reported recently (Usha et al.

1992). The incidence of classic PKU in Kuwait was found to be 1:6,479 livebirths

as estimated in the course of a neonatal screening project, versus the North

American incidence of 1:11,000. The incidence of classic PKU in the United

Arab Emirates was found to be 1: 20,050 (Al-Hosani et al. 2003). On the other

hand, no case of PKU was detected among 70,000 newborns screened by Aramco

in the eastern province in Saudi Arabia, a nearby area (Abu-Osba et al. 1992).

However, at a referral center in Saudi Arabia, patients with Hyperphenylalaninemia

(HPA) secondary to 6-pyruvoyltetrahydropterin synthase deficiency were frequently

seen and appeared to be more common than classic PKU patients (Al-Aqeel et al.

1991; Ozand et al. 1992). Mutations and polymorphisms at the phenylalanine

hydroxylase (PAH) gene were studied in 36 Palestinian families in Israel (Kleiman

et al. 1994). Four mutations previously identified in Europe were found among the

Palestinians, indicating that gene flow from Europe into the Palestinian gene pool

could have occurred at previous periods in history. In addition, three PAH mutations

unique to Palestinian Arabs (IVSnt 2, ED(197-205) and R2705) were identified,

indicating high genetic diversity of this population. A study of patients from Kuwait

and Egypt showed the presence of four common European haplotypes, in addition to

four rare haplotypes and three unclassified ones (Bender et al. 1994). In addition, a

new MspI-polymorphism was found in one Egyptian family and one individual

control from Kuwait. The same polymorphism has been described in American

blacks (Hoffmann et al. 1991). This may indicate that the associated mutation

probably originated from Africa and spread within Africa to Arabia as well as to

America. Another study on Egyptian patients showed a high degree of molecular

heterogeneity at the PAH locus (Effat et al. 1999). From Paris, 26 families with at

least one child affected with HPA were studied together with 100 unrelated families

from North Europe and the Mediterranean region (Berthelon et al. 1991). An

exclusive or preferential linkage disequilibrium between a particular haplotype and

PAHmutation with clear geographic partitioning of the mutations was observed. The

spectrum of mutations commonly observed in North European populations differed

from that observed among patients from the Mediterranean with specificity within

this group; interestingly, the majority of North African patients were homozygous

cases rather than compound heterozygote states. A novel specific mutation, Glu!lys

at codon 280, was identified in endogamous North African families, and it was later

12 A.S. Teebi

demonstrated to be the most frequent in the whole Maghreb (Lyonnet et al. 1989).

This mutation was also identified in a French family, thus raising the question of a

relation with the Arab invasion of France during the seventh century AD (Lyonnet

et al. 1989). In another study (Benit et al. 1994), novel frame shift deletions were

found in two Arab patients from north Africa. One of these patients had a 22 bp

deletion previously described in an Arab patient from Israel (Kleiman et al. 1994).

Other Inborn Errors of Metabolism

Homocystinuria is among the common aminoacidopathies observed in Saudi

Arabia and Kuwait (Ozand et al. 1992; Teebi 1994; Al-Essa et al. 1998). Recently,

the incidence homocystinuria in Qatar was found to be greater than 1 in 3,000,

representing the highest incidence in the world (El-Said et al. 2006). Based on

figures from the national neonatal screening program, the incidence of homocysti-

nuria among the National Qatari newborns was 1 in 1,400. Other frequently

diagnosed disorders include branched-chain aminoaciduria (MSUD) in classic

and intermediate forms (Ozand et al. 1992), non-ketotic hyperglycinemia, cystin-

uria, tyrosinemia type I and tyrosinemia type II (Hashem 1982; Yadav and Reavey

1988; Teebi 1994; Charfeddine et al. 2006).

Urea cycle defects, in particular the autosomal recessive types, are also common.

Among these are Citrullinemia, Argininosuccinic aciduria and Carbamoyl phos-

phate synthase deficiency (Yadav and Reavey 1988; Issa et al. 1988b).

Organic acidemias, namely Methylmalonic acidemia, 3-Hydroxyl-3-methylglu-

taryl coenzyme A lyase deficiency and Propionic acidemia are common (Ozand

et al. 1992; Teebi 1994; Rashed et al. 1994). Methylmalonic acidemia and other

organic acidopathies were found to have characteristic tribal occurrence in Saudi

Arabia (Ozand et al. 1992) and other Gulf countries. Also, they were found to have

high frequency among the Palestinians (Zlotogora 1996, personal communication).

Lysosomal storage disorders (LSD) constitute a large sector of the diagnosable

neurometabolic disorders among the Arabs in Kuwait, Saudi Arabia, Egypt and

Israel. Among the commonly diagnosed conditions are the Hurler and Hurler–

Scheie syndromes, Morquio syndrome, Maroteaux-Lamy syndrome, Sanfilippo

syndrome – type B, GM1 gangliosidosis, GM2 gangliosidosis – Sandhoff variant,

multiple sulfatase deficiency, ceroid lipofuscinosis, Niemann Pick – types A, B, and C,

Canavan disease, Metachromatic leucodystrophy, Krabbe disease, Gaucher disease –

neuropathic type and Neuroaminidase deficiency (Hashem 1982; Ozand et al.

1990a, b, 1992; Teebi 1994). A new variant of multiple sulfatase deficiency,

which differs clinically from the classic neonatal, childhood and juvenile-onset

multiple sulfatase deficiency, was described in eight Saudi patients. (Al-Aqeel et al.

1992). Some of these disorders have shown definite tribal occurrence and might

even be restricted to certain Bedouin tribes or large kindred. They include GM2

gangliosidosis – Sandhoff’s variant, mucolipidosis Sanfilippo’s syndrome – type B,

Canavan disease, neuroaminidase deficiency and Niemann-Pick – type C.

1 Introduction: Genetic Diversity Among Arabs 13

Metachromatic leucodystrophy was found to be more frequent among Arabs

living in two restricted areas in Israel (Heinisch et al. 1995). While multiple

mutations are responsible for this high frequency, a single origin for the most

frequent mutation was found (Zlotogora et al. 1994a). It is suggested that this

mutation may have been introduced into Jerusalem at the time of the Crusades.

Among the Arab Druze community in Israel, Hurler syndrome and mucolipidosis –

type III are highly prevalent (Zlotogora, personal communication).

Tay-Sachs disease is a common disorder among the Jews, particularly Ashke-

nazis and Moroccan Jews, but rarely described among Arabs (Jacoub 1938; Navon

et al. 1981). In Kuwait, at least three families were found to have one or more

affected members (Farag et al. 1993a; Teebi 1994; Shaabani et al. 2010), and in

Egypt, six families were ascertained in one center in Cairo (Hashem 1982).

Recently, an Israeli Arab with Tay-Sachs disease was found to have G786A

transition in the HEX A gene (Drucker and Navon 1993). This specific mutation

was originally described in a British infantile patient (Triggs-Raine et al. 1991),

which raises the question of whether this mutation was introduced into Palestine

during the Crusades or is a recurrent mutation.

Molecular studies on Arab patients with LSD have shown wide ranges of

causative mutations (Bargal et al. 2006; Brautbar et al. 2008; Kaya et al. 2008a, b)

Dyggve–Melchior–Clausen disease, a condition resembling Morquio syndrome

in some aspects, was suggested to have a high gene frequency in the Lebanese

(Naffah 1976; Bonafede and Beighton 1978) and Lebanese from Montreal. It was

also described in Moroccan Jews and Palestinians from Gaza (Schorr et al. 1977.

Glycogen storage disorders, notably types I & III, are commonly diagnosed in

several parts of the Arab world.

Other relatively common disorders are fatty acid oxidation defects, in particular

VLCAD in Saudi Arabia. MCAD incidence was found to be close to that of the

Caucasians, with one mutation identified in 72% of cases (Al-Hassnan, personal

communication 2009).

Primary hyperoxaluria type 1 is particularly frequent in Tunisia, where it was

described in 23 cases (Ben Moussa et al. 1993). On the other hand, classic congenital

adrenal hyperplasia due to 21 hydroxylase defiency was found to be more frequent in

Kuwait than in Europe and Canada (Lubani et al. 1990). Vitamin D-dependent rickets

type I and Wilson disease are also apparently common in Kuwait (Teebi 1994).

Cystic Fibrosis and Congenital Chloride Diarrhea

Although rare in blacks and Asians, Cystic fibrosis (CF) is the most common lethal

genetic disease in the Caucasian populations. In this sense, the old belief that CF is

rare or non-existent in Arabs, who are Caucasian by descent, is surprising. The first

report on CF in Arabs came from Lebanon (Salem and Idrees 1962). This

was followed by reports from other Arab countries (Al-Hassani 1977; Aluwihare

et al. 1981; Kamal and Nazer 1984; Kolberg 1986; Nazer et al. 1989; Farag and

14 A.S. Teebi

Teebi, 1989b; Dawson and Frossard 1994). The diagnosis was often missed because

of mild manifestations or atypical presentation with metabolic alkalosis in the

Arabian Peninsula’s hot and humid weather (Issa et al. 1988a; Mathew et al.

1991), or because many deceased infants were labeled as having succumbed to

gastrointestinal and/or respiratory infections, the two leading causes of infant

deaths in Arab children. Recent data concerning CF have shown that the estimated

incidence among Arab populations ranges from 1/2,188 to 1/4,243 livebirths; these

are similar to figures from Europe and North America. A study of 70 patients from

46 families from Saudi Arabia has identified eight novel mutations, with1548delG

being the most prevalent (Banjar et al. 1999; Kambouris et al. 2000). In a Bedouin

tribe from Qatar with approximately 40,000–50,000 people, at least 70 children

were documented to have CF, accounting for an incidence higher than 1 in 1,000

Qatari-livebirths. All patients belonging to this tribe have homozygous I1234V

mutation in exon 9 of CFTR gene (Abdul Wahab et al. 2001). This extremely high

incidence of CF with a single mutation provides a classical example of genetic drift

due to a Founder effect.

Data from Israel have shown that the DF508 mutation, which accounts for

approximately 70% of all CF chromosomes in a worldwide survey, was found to

account for 22–25% of CF chromosomes in Palestinians and Israeli Arabs (Lerer

et al. 1990; Shoshani et al. 1992). Four mutations (DF508, G542X, W1282X and

N1303K) accounted for 55% of the CF alleles in Arab patients (Abeliovich et al.

1992). In a study of 38 Tunisian families, the common allele was DF508, account-ing for 18.4% of CF chromosomes. In addition, several other mutations were found

at lower frequencies, including a few new mutations and a strikingly high number

of true homozygotes of rare alleles. In the UAE, eight unrelated patients were all

observed to have the same S549R mutation (Frossard et al. 1994), a rare mutation

previously observed in a Jewish family from Israel (Kerem et al. 1990). In Kuwait,

a Bedouin family of three affected individuals was studied for six CF mutations

(DF508, D1007, G542X, S549N, G551D and R553X). Of these mutations, none

was detected in this family (Farag et al. 1994b).

Wei et al. (2006) performed carrier screening on 805 Arab-Americans, testing

for at least the original 25 mutations recommended by the American College of

Medical College. The observed carrier frequency was 1 in 115; this could be an

underestimate due to the expected rare and novel mutations, specific to the popula-

tion, that were not in the panel of testing.

Congenital Chloride Diarrhea (CLD) is a rare and treatable autosomal recessive

disorder of chloride transport that was diagnosed in 16 Kuwaiti patients, mostly

Bedouins. The incidence was estimated to be 7.6/100,000 livebirths, which is

similar to that in Finland (Lubani et al. 1989; Badawi et al. 1998). In a study

from Saudi Arabia (Kagalwalla 1994), a remarkably high incidence of 1/5,500

livebirths was observed. Thus far, all reports of Arab patients with CCD came from

the Arabian Peninsula, suggesting that this condition is especially common there

(Kagalwalla 1994). Allelic diversity of CLD was studied in high incidence popula-

tions of Poland, Finland, Saudi Arabia and Kuwait. A major founder effect was

found in Arab patients (Hoglund et al. 1998).

1 Introduction: Genetic Diversity Among Arabs 15

Osteopetrosis Syndromes

Data from Saudi Arabia indicate that the severe autosomal recessive form of osteo-

petrosis is common in the Arabian Peninsula (Mahdi 1988; Abdel-Al et al. 1994).

The estimated minimum prevalence appears to be higher than in other countries

(Abdel-Al et al. 1994). Osteopetrosis with renal tubular acidosis and cerebral

calcification due to carbonic anhydrase II deficiency has been reported frequently

in the Arabian Peninsula and the Maghreb countries (Ohlsson et al. 1986; Bejaoui

et al. 1991; Al-Rasheed et al. 1998), and in fact 72% of the cases reported were

Arabs (Fathallah et al. 1994). Among the four mutations described, a splice junction

mutation at the 50 end of intron 2 in the CA II gene was reported to underlie the

molecular defects of this syndrome in six Arab kindred from various countries (Hu

et al. 1992). A recent study of ten Tunisian patients revealed that they were

homozygous to the same unique mutation (Fathallah et al. 1994); this mutation

appears to be confined to Arabs.

Persistent Hyperinsulinemic Hypoglycemia

Also called Nesidioblastosis of Pancreas (NP), it is an autosomal recessive disorder,

frequently diagnosed among Bedouin and nationals of Saudi Arabia and Kuwait.

Glaser et al. (1990) described seven pedigrees from Israel, including a large

Bedouin family and an Arab family. In a Saudi population with high consanguinity

rate, Mathew et al. (1988) established the incidence as 1/2,675 livebirths, compared

to 1/50,000 in a randomly mating population (Bruining 1990). A large number of

families were also reported in Saudi Arabia (Cherian et al. 1994; Bin-Abbas et al.

2003; Cherian and Abduljabbar 2005; Karawagh et al. 2008). Also, it was reported

in Bedouin children from Kuwait (Ramadan et al. 1999). Thomas et al. (1995) used

the homozygosity mapping strategy to localize the mutation for this disorder on 11p

in five consanguineous Saudi Arabian families.

Sanjad-Sakati Syndrome

The syndrome of congenital hypoparathyroidism, mental retardation, facial dys-

morphism and extreme growth failure (HRD) or Sanjad-Sakati syndrome is a

relatively common autosomal recessive disorder reported almost exclusively

among the Arabs mainly from Saudi Arabia, Kuwait, Israel and Palestinian terri-

tories (Sanjad et al. 1991; Marsden et al. 1994; Parvari et al. 2002; Hershkovitz

et al. 2004; Naguib et al. 2009). Data suggest that a common founder mutation of

TBCE gene accounts for Arab patients (Hershkovitz et al. 2004; Naguib et al.

2009). Preimplantation diagnosis was possible as a tool for the prevention of the

disease in Saudi Arabia (Hellani et al. 2004).

16 A.S. Teebi

Malformation Syndromes

When considered collectively, malformation syndromes are common; individually,

however, they are extremely rare. Nonetheless, a few autosomal recessive malfor-

mations appear to be common in Arab countries. Bardet-Biedl syndrome (BBS), for

example, is common in Kuwait, particularly among the Bedouin, Kuwaiti, Syrian

and Palestinian populations (Farag and Teebi, 1988a). The estimated prevalence

among the whole Bedouin community is 1/13,500, about 15 times higher than that

of Switzerland. The incidence of BBS among Bedouins in a small geographic area

was 1/6,900 livebirths (Farag and Teebi, 1989a). Similar findings were noted in

Bedouin tribes and Palestinian Arabs (Leitersdorf et al. 1994; Zlotogora 1997).

BBS also appears to be common in Egypt, Lebanon and Israel. Another very

common disorder is Meckel syndrome, which has an incidence of at least 1/3,530

livebirths in Kuwait (Teebi et al. 1992). High frequencies of Meckel syndrome

were reported also among Tatars (Lurie et al. 1984) and in Gujarati Indians (Young

et al. 1985).

Multiple pterygium syndrome is a frequently diagnosed disorder in Kuwait,

Saudi Arabia, and Qatar. An estimated prevalence of 1/31,000 was found in the

general population in Kuwait (Teebi and Daoud 1990). Autosomal recessive hydro-

cephalus of prenatal onset was found to be common among Palestinian Arabs in

Kuwait and Israel (Teebi and Naguib 1988; Zlotogora et al. 1994b; Zlotogora

1997). On the other hand, autosomal recessive microcephaly with normal intelli-

gence or associated with mental retardation and severe neurologic defects appears

to be common among various Arab communities in Kuwait, Saudi Arabia

and Qatar.

Familial intestinal atresias, particularly the apple-peel variant, and the autosomal

recessive congenital diaphragmatic hernia are not uncommon based on reports from

Lebanon and Kuwait (Mishalany and Najjar 1968; Mishalany and Der Kaloustian

1971; Farag et al. 1993b, 1994a).

Xeroderma Pigmentosum

Xeroderma Pigmentosum (XP) appears to be common in several Arab countries,

including Kuwait, Lebanon, Syria, Iraq, Jordan, the Palestinian territories Egypt,

UAE and the Maghreb countries (German et al. 1984; El-Hayek et al. 2004; Zghal

et al. 2005). Molecular studies are available from some countries, some of which

have confirmed potential founder effect by haplotype analysis in Tunisian patients

(Matsumura et al. 1995; Falik-Zaccai et al. 2006; Ben Rekaya et al. 2009). The

prevalence is unknown but the disease accounts for 9–14% of childhood malig-

nancies in Tunisia (Miller 1977; Maalej et al. 2007). This is partly due to an

environmental effect owing to the sunny climate in that region.

1 Introduction: Genetic Diversity Among Arabs 17

Non-Syndromic Deafness

Non-syndromic deafness is very common among Arabs. It is not unexpected that

the majority of the cases belong to the autosomal recessive inheritance, a remark-

ably heterogeneous group.

In a large Palestinian kindred originating from the West Bank, 13 cases in

several sibships were reported to have uncomplicated profound deafness from

early infancy (Kabarity et al. 1981). High incidence of profound deafness reaching

2% of the inhabitants of a Palestinian/Israeli village was documented (Zlotogora

and Barges 2003). Most cases were due to mutations in Connexin-26 gene. A large

Israeli–Arab pedigree with sensorineural deafness was determined simultaneously

by two loci-one mitochondrial and one autosomal recessive (Jaber et al. 1992;

Bu et al. 1993). Further studies in the same family and three unrelated families with

aminoglycoside-induced deafness showed an A-to-G transition at nucleotide 1,555

in the 12 S r-RNA gene (Prezant et al. 1993). This mutation is responsible for

antibiotic-induced ototoxity as well as non-syndromic deafness. Other studies

among the Palestinians and Bedouin in Israel have shown high incidence of

prelingual deafness with remarkable genetic heterogeneity (Fischel-Ghodsian

et al. 1995; Scott et al. 1996; Shahin et al. 2002; Walsh et al. 2006).

In Tunisia, sensorineural deafness became an active area of research in the last

few years. Several autosomal recessive genes and many mutations have been

identified. Data from Northern Tunisia have shown that the prevalence of nonsyn-

dromic deafness ranges between 2% and 8% in the isolates there (Ben Arab et al.

2004). Evidence for genetic heterogeneity was provided, even within isolates.

However, the most frequent was the 35delG mutation of GJB2 gene (Ben Arab

et al. 2000, 2004).

Somewhat similar circumstances related to high frequencies of nonsyndromic

deafness in relation to consanguinity and isolation are also found in other Arab

countries (Al-Gazali 1998; Tabchi et al. 2000; Al-Khabori and Khandekar 2004).

Osteochondrodysplasias

Skeletal dysplasia are frequently diagnosed in the Arab world, though the delinea-

tion needs an expert opinion in many instances.

A study from UAE has shown that 36 out of 38,046 births had some type of

skeletal dysplasia (almost 1:1,000) (Al-Gazali et al. 2003). Half of them (18) were

attributed to autosomal recessive genes. The most common recessive type was

fibrochondrogenesis followed by chondrodysplaia punctata. An unpublished study

from Qatar showed an incidence of 5:1,000 births, which is half of the UAE figure.

Lethal chondrodystrophies were frequently diagnosed as well.

Other relatively common skeletal/connective tissue disorders include the spondy-

loepiphyseal dysplasia tarda with progressive arthropathy (Teebi and Al-Awadi 1985;

18 A.S. Teebi

Hurvitz et al. 1999) in Jordan and Lebanon, Stueve_Wiedemann syndrome

(Langer et al. 2007) in the UAE and an arterial tortuosity syndrome with skeletal

manifestations in Qatar and Saudi Arabia (Al Fadley et al. 2000; Faiyaz-Ul-

Haque et al. 2008, 2009)

Genetic Predisposition to Non-disjunction

A study from Kuwait (Alfi et al. 1980) showed that Down syndrome (DS) was four

times more frequent among the children of closely related parents (p > 0.005).

Another study from Kuwait (Naguib et al. 1989) suggests an association between

consanguinity and occurrence of non-disjunction, though a single gene effect was

not observed. The other study from Kuwait showed a DS incidence of 4.5/1,000

livebirths in an area inhabited mainly by Bedouins, whereas in an area with a mixed

Arab population, the incidence was 1.7/1,000 livebirths (Farag and Teebi 1988b).

A remarkably higher incidence of DS was noted in the higher inbreeding coefficient

group with nearly similar maternal ages, suggesting the existence of some recessive

elements predisposing to non-disjunction. Comparable high frequencies of DS were

also reported from West Jerusalem and among the Negev Bedouins in Israel

(Harlap 1974; Abeliovich et al. 1986). It is not uncommon to find examples of

recurrent aneuploidies in the same family among the Bedouins in Kuwait or other

locations (Farag and Teebi 1988b; Krishna Murthy and Farag 1995). This may

provide support to the hypothesis of existence of a recessive gene or genes

controlling non-disjunction. Recently, based on a case report of a child with DS

and neural tube defect, it was suggested that the altered folate status plus homozy-

gous mutation of the MYHFR gene in the mother could promote chromosomal

instability and meiotic non-disjunction resulting in trisomy 21 (Al-Gazali et al.

2001).

Male Pseudohermaphroditism

Familial male pseudohermaphroditism (MPH) due to defects in steroid metabolism

or due to persistent mullerian duct syndrome are common among the Arabs (Rosler

et al. 1992; Farag 1993; Al-Attia 1997; El-Gohary 2003). MPH due to 17-b-hydroxysteroid dehydrogenase 3 deficiency is particularly common in Palestinian

territories and the Gaza Strip. Eighty-five males with this disorder were identified

among Palestinians and 57 studied over 25 years. The founders of this defect

originated in the mountainous regions of Lebanon and Syria, but most of the

families live in Jerusalem, Hebron, the Tel-Aviv area, and Gaza, where the fre-

quency of affected males is estimated at 1 in 100 to 150 (Rosler 2006).

1 Introduction: Genetic Diversity Among Arabs 19

Other Disorders Frequently Diagnosed Among Arabs

Autosomal recessive epidermolysis bullosa, Cutis laxa, Wrinkly skin syndrome,

Gerodermia osteodyslastica, autosomal recessive icthyosis and mal de meleda are

among the relatively common genodermatosis syndromes.

Clinical anophthalmia or nonsyndromic microphthalmia with CHX10 mutations

is prevalent in Gaza and Qatar with clear founder effect in one Qatari tribe (Kohn

et al. 1988; Bar-Yosef et al. 2004; Faiyaz-Ul-Haque et al. 2007).

Cytochrome b5-reductase deficiency was found to be prevalent in Algeria,

mostly in the south, with a heterozygous frequency of 3% (Reghis et al. 1981).

Homozygous cases are associated with cyanotic methemoglobinemia with or with-

out mental retardation and neurologic impairment (Vieira et al. 1995).

Glanzmann thromboasthenia was described in 12 Jordanian patients in 9 families

(Awidi 1983). A founder mutation was found to predominate in Palestinian patients

(Rosenberg et al. 2005). It was found to be frequent among the Iraqi Jews and Arabs

in Israel (Coller et al. 1987; Kannan and Saxena 2009).

Brain or CNS malformations are frequently diagnosed; they have received some

attention in the past few years. Several new forms have been delineated so far.

Several examples of study cohorts are available.

Homozygosity for the two autosomal recessive traits in the same sibship is not

rare. Numerous examples were observed in the highly inbred population of Kuwait,

particularly among the Bedouins. Some of these examples were recorded (Teebi

1994).

Autosomal Dominant and X-Linked Disorders

Apart from the apparent rarity of Huntington disease and the increased frequencies

of homozygotes for familial hypercholesterolemia, the pattern and apparent fre-

quencies of autosomal dominant disorders in Arab countries are not remarkably

different from those in Western countries.

On the basis of studies in Lebanon, Khachadurian (1964) first established the

existence of homozygous familial hypercholestrolemia (FHC). In Lebanon the

frequency of FHC homozygotes due to low-density lipoprotein receptor gene defect

is more than ten times higher than in other parts of the world (Lehrman et al. 1987).

Presumably, this is the result of an increased rate of consanguinity as well as a high

frequency of the trait. The allele was named the Lebanese allele and was also found

in patients from Syria, as well as in five Christian Arab kindred from Israel

(Oppenheim et al. 1991). Several other mutations were found among Arabs and

named according to the country of origin or community from which the patients

came from; they include FH Bahrain, FH Syria, FH Algeria, FH Kuwait, FH Druze,

etc. (McKusick 1994). In Kuwait the frequency of homozygotes of FHC was found

to be 1/23,000 in a mostly Bedouin population (Palkovic et al. 1994). Of the 502

20 A.S. Teebi

screened card samples from the same population, ten neonates were detected with

total cholesterol over the 98th percentile (unpublished data).

An autosomal dominant example of a new syndrome originally described is the

hypertelorism syndrome resembling craniofontonasal dysplasia, found in an Iraqi

kindred with 16 affected individuals living in Kuwait (Teebi 1987). The same

diagnosis was subsequently reported in Caucasian and black families from the

USA (Stratton 1991; Toriello and Delp 1994; Tsai et al. 2002; Han et al. 2006),

Japan (Tsukahara et al. 1995), Germany (Koenig 2003) and South America

(Machado-Paula and Guion-Ameida 2003).

Glucose-6-phosphate dehydrogenase deficiency (G6PD) is an example of an

X-linked disorder that has a special importance in the Arab world. The trait has

polymorphic frequencies throughout the region with wide variations ranging from

0.02 and 0.03 in Jordan, parts of Saudi Arabia and Lebanon to 0.58 among the

Kurdish Jews and 0.65 in the Qatif oasis in Saudi Arabia (Kurdi-Heidar et al. 1990).

The latest figures are the highest in the world (Sheba et al. 1961; El-Hazmi et al.

1986). G6PD-Mediterranean, a common variant in the Middle East, is characterized

by severe enzyme deficiency underlying not only acute hemolytic crisis following

the ingestion of fava beans (a popular meal in the Middle East), but also neonatal

jaundice and acute hemolytic anemia triggered by drugs or infection. Studies from

Oman, a country with frequency of G6PD deficiency of 0.25–0.27 in males and

0.10–0.11 in females (White et al. 1993; Daar et al. 1996; Al-Riyami and Ebrahim

2003), showed that despite such high frequencies, the oxidative hemolytic syn-

dromes are very uncommon, supporting earlier findings reviewed and stressed by

Beutler (1991).

Kurdi-Heidar et al. (1990) concluded that the large majority of Middle Eastern

subjects with G6PD-Mediterranean may have the same mutation found in Italy and

that the mutation probably arose on a chromosome that already carried the silent

mutation, an independent polymorphism in the Middle East.

Interest in the Genetic Disease Among Arabs

It had been my hope that the first edition of this book would stimulate interest

and research in the Arab world on this important set of diseases prevalent among

the Arabs, with a view to potential preventability. Soon after its publication, interest

began to foment with the formation of Middle East Genetic Association of

America, which held its first scientific meetings in Tunisia in December 1997

(Fathallah et al. 1998) and in Egypt in 1999 (Teebi and Shawky 2000). This was

followed by the establishment of the first curated Arab Genetic Disease Database

based at the Hospital for Sick Children in Toronto. This was in response to Human

Genome Organisation Initiative to establish ethnic genetic databases (Teebi et al.

2002) (This database was later discontinued due to lack of funding). In 2005,

a different database was formed in Dubai (Tadmouri et al. 2006). The interest

in genetic disease among the Arabs is continuing and receiving wide attention

1 Introduction: Genetic Diversity Among Arabs 21

internationally, and has given rise to a better understanding of the prevalent

disorders, the establishment of collaborations with many first class world-centers

and an improvment in quality and quantity of publications.

I hope that we are able to continue stimulating active research in the many

aspects of Arab genetic disorders, including their characterization, frequencies

and distribution, molecular bases, pathogenesis and origins. Genetic services and

research in the field of medical genetics are still far from being adequate in many

parts of the Arab world (Teebi and Teebi 2005; Al-Gazali et al. 2006). Genetic

diversity among Arabs, high rates of inbreeding and large family size are optimal

for the manifestation of many autosomal recessive disorders (Teebi and El-Shanti

2006). There is little doubt that genetic disease from this part of the world has the

potential of becoming a major area of research, one that has the potential to benefit

mankind at large.

This Edition

This is the second edition of the book “Genetic Disorders Among Arab Popula-tions”, first published by Oxford University Press in 1997. Rather than provide the

reader with an exhaustive list of genetic disorders among the Arabs, our intention in

this book is to highlight the prevalent conditions, genes and mutations involved, the

frequencies of diseases and mutations when available, their characteristics and the

global pattern of genetic disorders at large and the contributing factors. In addition,

we discuss the attitudes of people toward both genetic counseling and the available

options on the ground, options that are influenced by the Islamic perspective.

Indeed, the attitudes are largely affected by the culture and faith of the Arabs and

are remarkably different in many aspects from those of the Western world.

To achieve these goals, I have designed this book with four major sections. After

the introductory chapter, an overview of the monograph, the first section contains

three chapters dealing with the unique demographic and economic characteristics in

the Arab world. In addition to population dynamics and health indicators, endo-

gamy and consanguinity are also discussed as prominent demographic features of

great importance among Arabs.

The second section contains three chapters discussing in some detail selected

common entities: autoinflammatory disorders including FMF, muscular dystrophies

and myopathies, and new syndromes first reported among Arabs.

Fourteen Arab countries or geographic regions are represented in the 15 chapters

of the third section, with the aim of discussing aspects of genetic disease in each.

These entities include the Jews from Arab countries, in addition to a chapter

discussing genetic disorders in ancient Egypt. For the purpose of avoiding redun-

dancy, a separate chapter on Bedouins has been omitted from this edition, as much

of the data are provided in the chapters on Saudi Arabia, Kuwait, Qatar, Oman,

UAE and Palestine. Although some aspects of genetic disease in other countries

such as Syria, Yemen, Mauritania and Somalia can be found in other chapters,

22 A.S. Teebi

they are not included in this section owing to the extreme scarcity of genetic infor-

mation from them.

The fourth section includes two chapters examining issues related to the preven-

tion and care of genetic disorders from an Islamic perspective, as well as the related

issue of genetic counseling in the Middle East, including its medical, genetic and

psychological implications and real, everyday practice.

Genetic information generated so far from some Arab countries provides a

valuable indicator of the prevailing disorders in the Arab world at large. However,

such information is quite fragmentary in several other parts of the Arab world. It is

often largely based on case reports and case series studies, rather than prospective

epidemiological and molecular studies. Nonetheless, it is felt that such information

is useful, as it well emphasizes the points of weakness and strength in the available

knowledge, as well as what could be done to improve it. In comparison with the first

edition, data in this book show that the research has certainly taken a remarkable

step forward.

The book has been mostly re-written and in some chapters, the information has

been extensively revised and updated. A large part of the book was written by a new

generation of experts in the field. The reader will recognize the genetic diversity

among the Arabs from the varied clinical phenotypes and genotypes within the

same region or country and or between individual Arab Countries.

The information provided here will prove beneficial to those planning to imple-

ment health services in the Arab world, as well as to national and international

bodies that provide advice to these. It will also helpf physicians and medical

students in the Arab world who are confronted with the varied aspects of genetic

disease. Physicians in the West who encounter Arab patients as immigrants or

seeking help in specialized centers will also find this book useful.

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