Genetic Disorders Among Arab Populations

.

Ahmad S. TeebiEditor

Genetic Disorders AmongArab Populations

Second Edition

EditorAhmad S. TeebiWeill Cornell Medical College in QatarQatar FoundationDohaEducation CityQatarast2003@qatar-med.cornell.edu

First edition published by Oxford University Press, 1997.

ISBN 978-3-642-05079-4 e-ISBN 978-3-642-05080-0DOI 10.1007/978-3-642-05080-0Springer Heidelberg Dordrecht London New York

Library of Congress Control Number: 2010932676

# Springer-Verlag Berlin Heidelberg 2010This work is subject to copyright. All rights are reserved, whether the whole or part of the material isconcerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting,reproduction on microfilm or in any other way, and storage in data banks. Duplication of this publicationor parts thereof is permitted only under the provisions of the German Copyright Law of September 9,1965, in its current version, and permission for use must always be obtained from Springer. Violationsare liable to prosecution under the German Copyright Law.The use of general descriptive names, registered names, trademarks, etc. in this publication does notimply, even in the absence of a specific statement, that such names are exempt from the relevant protectivelaws and regulations and therefore free for general use.

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Springer is part of Springer Science+Business Media (www.springer.com)

To my parents, brothers and sisters, and my children Saeed, Basel, Asil and Asmaand the whole Arab Family.

.

Acknowledgements

The editor is grateful to the authors of the individual chapters who welcomed the

initiative and were keen to provide their contributions on time. Special thanks to

Professor Charles R. Scriver, who made the effort to write the foreword to this

book. I am thankful to my wife Mrs. Amal Teebi for her encouragement and support

and to Saeed Teebi for his assistance in some parts of the manuscript.

The assistance of Mrs. Mariette D’ Souza, Gemma Fabricante and Martin

Marion from Weill Cornell Medical College in Qatar, in preparation of some

chapters and maps, is greatly appreciated.

I express my gratitude also to Springer press and in particular to Andrea Pillman

and Ursula Gramm for their help in the publication of this book.

vii

.

Foreword

Genetic Disorders among Arab Populations by Ahmad S. Teebi and co-authors

appears here in its second edition. The first edition (in 1997) shows how one could

tap into a rich load of information on human and medical genetics, a source

probably too little mined until now. One can be pleased that the first edition was

warmly welcomed by Prof. Victor McKusick, the author of the Foreword to that

edition. The authors of this edition have taken pains to remind us again that persons

and patients, and the corresponding families and communities, represent a stream of

human history and a region of the world that embraces ethnic, cultural and religious

attributes more diverse than we might have imagined, yet with a commonality that

gives “coherence to an account of it and a usefulness [when it is considered] as a

unit” (VA McKusick, Foreword to first edition).

Arab populations have their repertoire of genetic disorders, both universal and

particular. Genetic diversity within these source populations, along with the fact

that rates of inbreeding are often high and family sizes are often large, constitutes

conditions that facilitate the emergence and detection of phenotypes explained

notably by autosomal recessive inheritance, in which case, the use of homozygosity

gene mapping will facilitate discovery of the corresponding genes. Meanwhile, the

interval between the publication of the first and second editions of genetic disorders

has witnessed emergence of the Middle East Genetic Association of America and

the creation of ethnic (Arabic)-related, locus-specific mutation databases to serve as

nodes in the network of related interests. Driven by relevant research interests,

initiatives are emerging in the Arabic world to address issues such as taxonomy and

fine-grained descriptions of variant disease phenotypes, their origins, distributions

and frequencies in populations, their molecular infrastructure, and with a better

knowledge of their pathogenetic processes, better opportunities to address coun-

seling, prevention and treatment.

The authors of the second edition have again chosen not to provide an exhaustive

list of relevant genetic disorders; that can be done eventually when there is a curated

online database. Rather, the authors again highlight various issues and perspectives

that can be seen through the windows offered by a number of prevalent genetic

disorders in the Arabic world. Accordingly, the attitudes and responses generated

ix

by these problems, as they are influenced by Islamic perspectives, wisely constitute

the recurrent underlying theme in the book, because the cultures and faith of the

Arabic communities yield quite different responses and perspectives from the

corresponding encounters in the non-Islamic world. It is a particular form of a

larger issue attracting notice (viz. Suther and Kiros, Genet Med 11:655–662, 2009;

Krotoski et al. Genet Med 11:663–668, 2009).

The authors use prevalent, pan-Arabic disorders (Table 1.1), along with a

selection of rarer “founder” disorders (Table 1.2), to delve into the biological

explanations for their occurrence and impact. These disorders set the scene to

explain important demographic issues, the related population dynamics, indicators

of individual collective health, and the impacts of endogamy and consanguinity on

the frequencies and distribution of the disorders. Familial Mediterranean Fever, for

example, illustrates these perspectives well and is highlighted accordingly. The

authors examine 15 different countries and regions harbouring Arabic populations,

to discern issues with more specific aspects. One might say that in this diversity,

there is a unity and vice versa. Consolidations of the expanding information on

genetic disorders in Arabic populations improves our knowledge of them. Whether

that leads to better wisdom, in how we help the individuals, families and commu-

nities harboring them, is, I am convinced, a sincere motivation to pursue the course

undertaken by Professor Teebi and his co-authors. It has indeed yielded this

enhanced second edition of Genetic Disorders among Arab Populations.

Charles R. Scriver MDCM FRS

Alva Professor Emeritus of Human Genetics

Professor of Pediatrics and Biology

McGill University

Montreal, Canada

x Foreword

Contents

Part I Introduction

1 Introduction: Genetic Diversity Among Arabs . . . . . . . . . . . . . . . . . . . . . . . . . . 3

Ahmad S. Teebi

Part II Demography, Economy, and Genetic Services in Arab Countries

2 Arab Demography and Health Provision . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37

Sulayman S. Al-Qudsi

3 Influences of Systems’ Resources and Health Risk Factors on Genetic

Services . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 65

Amal A. Saadallah and Ahmad S. Teebi

4 Endogamy and Consanguineous Marriage in Arab Populations . . . . . . 85

Alan H. Bittles and Hanan A. Hamamy

Part III Selected Disease Entities Prevalent Among the Arabs

5 Familial Mediterranean Fever and Other Autoinflammatory

Disorders . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 111

Hatem El-Shanti and Hasan Abdel Majeed

6 Muscular Dystrophies and Myopathies in Arab Populations . . . . . . . . . 145

Mustafa A.M. Salih

7 New Syndromes First Reported Among Arabs . . . . . . . . . . . . . . . . . . . . . . . . 181

Ahmad S. Teebi

xi

Part IV Genetic disorders in Arab Countries Geographic Regions

8 Genetic Disorders in Egypt . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 219

Samia A. Temtamy, Mona S. Aglan, and Nagwa A. Meguid

9 Genetic Disorders in Ancient Egypt . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 273

Chahira Kozma

10 Genetic Diseases in Iraq . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 297

Hanan Ali Hamamy

11 Genetic Disorders in Jordan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 325

Majed Dasouki and Hatem El-Shanti

12 Genetic Disorders in Kuwait . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 353

Nawal Makhseed

13 Genetic Disorders in Lebanon . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 377

Vazken M. Der Kaloustian

14 Genetic Disorders in Libya . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 443

Tawfeg Ben-Omran

15 Genetic Disorders in Morocco . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 455

Abdelaziz Sefiani

16 Genetic Disorders in Oman . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 473

Anna Rajab

17 Genetic Disorders Among the Palestinians . . . . . . . . . . . . . . . . . . . . . . . . . . . 491

Bassam Abu-Libdeh and Ahmad Said Teebi

18 Genetic Disorders in Qatar . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 515

Ahmad S. Teebi and Tawfeg Ben-Omran

19 Genetic Disorders in Saudi Arabia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 531

Zuhair N. Al-Hassnan and Nadia Sakati

20 Genetic Disorders in Sudan . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 575

Mustafa A.M. Salih

21 Genetic Disorders in Tunisia . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 613

Elham Hassen and Lotfi Chouchane

xii Contents

22 Genetic Disorders in the United Arab Emirates . . . . . . . . . . . . . . . . . . . . . 639

Lihadh Al-Gazali and Bassam R. Ali

23 Genetic Disorders Among Jews from Arab Countries . . . . . . . . . . . . . . . 677

Efrat Dagan and Ruth Gershoni-Baruch

Part V Cultural and Religious Attitudes Towards Genetic Issues

24 Prevention and Care of Genetic Disorders: An Islamic

Perspective . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 705

Aida I. Al Aqeel

25 Genetic Counseling in the Middle East . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 725

Shelley J. Kennedy and Muna Al-Saffar

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 741

Contents xiii

.

Contributors

Hasan Abdel Majeed Professor Emeritus of Pediatrics, University of Jordan,

Amman, Jordan

Bassam Abu-Libdeh Makassed Hospital & Al-Quds University, Jerusalem,

drbassam@med.alquds.edu

Mona S. Aglan Professor of Clinical Genetics, Clinical Genetics Department,

Human Genetics and Genome research division, National Research Centre, Cairo,

Egypt, drmona_aglan@yahoo.com

Aida I. Al Aqeel Pediatrics, Medical Genetics and Endocrinology, Department of

Pediatrics, Riyadh Military Hospital, P. O. Box 7897, Riyadh 11159, Kingdom of

Saudi Arabia, alaqeela1@hotmail.com, aalaqeel@rmh.med.sa

Stem Cell Therapy Program, King Faisal Specialist Hospital and Research Centre,

P. O. Box 3354, Riyadh 11211, Kingdom of Saudi Arabia

Lihadh Al-Gazali Department of Paediatrics, Faculty of Medicine and Health

Sciences, UAE University, Al-Ain, United Arab Emirates, l.algazali@uaeu.ac.ae

Zuhair N. Al-Hassnan Associate Prof. of Genetics, College of Medicine, Alfaisal

University Consultant, Department of Medical Genetics, MBC-75, King Faisal

Specialist Hospital & Research Center, P.O. BOX 3354, Riyadh 11211, Saudi

Arabia, zhassnan@kfshrc.edu.sa

Bassam R. Ali Faculty of Medicine and Health Sciences, Department of

Pathology, UAE University, Al-Ain, United Arab Emirates

Sulayman S. Al-Qudsi Chief Economist and Head of Research Department-Arab

Bank, PLC. Amman-Jordan.Shaker bin Zeid Street, Shmeisani Area, 950545,

Amman, Jordan, sshqudsi@gmail.com; dr.sulayman.alqudsi@arabbank.com.jo

Muna Al-Saffar Certified Genetic Counsellor, Children’s Hospital Boston, MA,

USA

xv

Project Manager, Dubai Harvard Foundation for Medical Research (DHFMR),

Dubai Health Care City, Dubai, United Arab Emirates

Tawfeg Ben-Omran Section of Clinical and Metabolic Genetics, Qatar Medical

Genetics Center, HamadMedical Corporation,Doha, Qatar, tawben11@hotmail.com

Alan H. Bittles Centre for Comparative Genomics, Murdoch University, South

Street, Perth, WA 6150, Australia, abittles@ccg.murdoch.edu.au

Lotfi Chouchane Professor of Genetic Medicine and Immunology, Genetic

Medicine Department, Weill Cornell Medical College, Qatar, loc2008@qatar-med.

cornell.edu

Efrat Dagan Institute of Human Genetics, RAMBAM Health Care Campus and

Department of Nursing, University of Haifa, Haifa, Israel

Majed Dasouki Professor of Pediatrics & Internal Medicine University of Kansas,

Kansas City, Kanasa, USA

VazkenM. Der Kaloustian Emeritus Professor of Pediatrics and HumanGenetics,

Mchill University, Montreal, Quebec, Canada, vazken.derkaloustian@mcgill.ca

Hatem El-Shanti Director, Shafallah Medical Genetics Center, Doha, Qatar;

Adjunct Associate Professor of Pediatrics, University of Iowa, Iowa City, Iowa,

USA, elshantih@smgc.org.qa

Ruth Gershoni-Baruch Institute of Human Genetics, RAMBAM Health Care

Campus and the Ruth and Bruce Rappaport Faculty of Medicine, Technion-Insti-

tute of Technology, Haifa, Israel, rgershoni@rambam.health.gov.il

Hanan A. Hamamy Department of Genetic Medicine and Development, Geneva

University Hospital, Geneva, Switzerland (formely Al-Mustansiriyah Medical

College, Baghdad, Iraq), hananhamamy@yahoo.com

Elham Hassen Molecular Immuno-Oncology Laboratory, Faculty of Medicine,

Monastir, Tunisia, elham.hassen@isbm.rnu.tn

Shelley J. Kennedy Certified Genetic Counsellor, Ontario Newborn Screening

Program & Regional Genetics Program, Children’s Hospital of Eastern Ontario,

Ottawa, ON, Canada, shelleyjkennedy@yahoo.ca

Chahira Kozma Department of Pediatrics, Georgetown University Hospital, 3800

Reservoir Rd N.W., Washington DC, USA, kozmac@georgetown.edu; cck2@

gunet.georgetown.edu

Nawal Makhseed Department of Pediatrics, Jahra Hospital, Ministry of Health,

Kuwait, nmakhseed@yahoo.com

Samia A. Temtamy Professor of Human Genetics, Clinical Genetics Department,

Human Genetics and Genome, research division, National Research Centre, Cairo,

Egypt, samiatemtamy@yahoo.com

xvi Contributors

Anna Rajab Consultant Clinical Geneticist, Genetic Unit, Ministry of Health,

Sultanate of Oman, dranrajab@omantel.net.com

Amal A. Saadallah Medical College, Ain Shams University, Cairo, Egypt,

amalsaadalla@yahoo.com

Nadia Sakati Consultant, Department of Pediatrics, MBC-58, King Faisal

Specialist Hospital & Research Center, P.O. BOX 3354, Riyadh 11211, Saudi

Arabia

Mustafa A.M. Salih Division of Pediatric Neurology, Department of Pediatrics,

College of Medicine, King Saud University, Riyadh, Saudi Arabia, mustafa_salih05

@yahoo.com; mustafa@ksu.edu.sa

Abdelaziz Sefiani Department of Medical Genetics, National Institute of Heath/

University Mohammed V Souissi, Rabat 27, Avenue Ibn Batouta, BP 769, 11400,

Rabat, Morocco, sefianigen@hotmail.com

Ahmad S. Teebi Weill Cornell Medical College, Qatar Foundation, Doha, Qatar,

ast2003@qatar-med.cornell.edu

Samia A. Temtamy Professor of Human Genetics, Clinical Genetics Department,

Human Genetics and Genome research division, National Research Centre, Cairo,

Egypt, samiatemtamy@yahoo.com

Nagwa A. Meguid Profssor of Human Genetics, National Research Centre, Tahrir

street Dokki, Giza, Egypt, meguidna@yahoo.com

Contributors xvii

.

Part IIntroduction

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