WORKSHOP REPORT

Consanguineous , pearls and perils: Geneva International Consanguinity Workshop Report Hanan Hamamy, MD1, Stylianos E. Antonarakis, MD, DSc1, Luigi Luca Cavalli-Sforza, MD2, Samia Temtamy, MD, PhD3, Giovanni Romeo, MD4, Leo P. Ten Kate, MD, PhD5, Robin L. Bennett, DSc6, Alison Shaw, PhD7, Andre Megarbane, MD, PhD8, Cornelia van Duijn, PhD9, Heli Bathija, MD10, Siv Fokstuen, MD1, Eric Engel, MD1, Joel Zlotogora, MD, PhD11, Emmanouil Dermitzakis, PhD1, Armand Bottani, MD1, Sophie Dahoun, MD1, Michael A. Morris, DPhil12, Steve Arsenault, BSc13, Mona S. Aglan, MD3, Mubasshir Ajaz, BSc, MSc14, Ayad Alkalamchi, MD15, Dhekra Alnaqeb, MD16, Mohamed K. Alwasiyah, PhD17, Nawfal Anwer, MD, FIBOG18, Rawan Awwad, MS19, Melissa Bonnefin, BA, MA20, Peter Corry, MD, FRCPCH21, Lorraine Gwanmesia, MD1, Gulshan A. Karbani, BSc, MSc22, Maryam Mostafavi, MD1, Tommaso Pippucci, PhD23, Emmanuelle Ranza-Boscardin, MD1, Bruno Reversade, PhD24, Saghira M. Sharif, BSc, PGCLTHE25, Marieke E. Teeuw, MD26, and Alan H. Bittles, PhD, ScD27

Abstract: Approximately 1.1 billion people currently live in countries strong preferential culture of close kin marriages in many societies, and where consanguineous marriages are customary, and among them one among migrant communities in Western countries, merits an equiva- in every three marriages is between . Opinions diverge between lently detailed assessment of the social and genetic benefits of consan- those warning of the possible health risks to offspring and others who guinity in future studies. Genet Med 2011:13(9):841–847. highlight the social benefits of consanguineous marriages. A consan- Key Words: consanguinity, consanguineous , , guinity study group of international experts and counselors met at the , fertility, stillbirths, infant mortality, congenital disorders, Geneva International Consanguinity Workshop from May 3 2010, to genetic counseling May 7, 2010, to discuss the known and presumptive risks and benefits of close kin marriages and to identify important future areas for research on consanguinity. The group highlighted the importance of evidence- ealthcare providers and specialists have usually based counseling recommendations for consanguineous marriages and Hjudged the overall impact of consanguineous marriage as of undertaking both genomic and social research in defining the various being negative when assessed in terms of increased genetic risks influences and outcomes of consanguinity. Technological advances in to the offspring, as opposed to the potential social and economic rapid high-throughput sequencing and for the identification of benefits. A study group of international experts and counselors copy number variants by comparative genomic hybridization offer a met at the Geneva International Consanguinity Workshop from significant opportunity to identify genotype-phenotype correlations fo- May 3, 2010, to May 7, 2010,1 to discuss the known and cusing on autozygosity, the hallmark of consanguinity. The ongoing presumptive risks and benefits of close kin marriages and to identify important future areas for research on consanguinity. It has recently been suggested that , 1 From the Department of Genetic Medicine and Development, University of defined as the deleterious effects that result from matings be- Geneva Medical School, and University Hospitals of Geneva, Geneva, Switzerland; 2Stanford University Medical School, Center of Popu- tween related individuals, could be associated with epigenetic 2 lation Genetics, Institute of Molecular Genetics of the Italian National mechanisms rather than DNA sequence alterations. Most stud- Research Council, University of Pavia, Milano, Italy; 3Human Genetics and Genome Research Division, Clinical Genetics Department, National Re- search Centre, Cairo, Egypt; 4University of Bologna Medical School, Italy; 22The Leeds Teaching Hospitals, NHS Trust, Yorkshire Regional Genetic 5VU University Medical Center, Amsterdam, The Netherlands; 6Department Service, Department of Clinical Genetics, Leeds, United Kingdom; 23Labo- of Medicine, University of Washington Medical Center, Medical Genetics, ratorio di Genetica Medica, Dipartimento di Scienze Ginecologiche, Seattle, Washington; 7Ethox Centre, Department of Public Health, Univer- Ostetriche Pediatriche-Universita` di Bologna, Policlinico S. Orsola-Mal- sity of Oxford, United Kingdom, Oxford, United Kingdom; 8Medical Ge- pighi, Bologna, Italy; 24Laboratory of Human Embryology, Institute of netics Unit and Laboratoire Associe´ INSERM UMR_S910, Saint Joseph Medical , A*STAR, Singapore; 25Leeds Teaching Hospitals, Depart- University; Beirut, ; 9Department of Epidemiology and Biostatis- ment of Clinical Genetics, Chapel Allerton Hospital, Leeds, United King- tics, Erasmus University Medical School, Erasmusmc, Rotterdam, The Neth- dom; 26VU University Medical Center, Department of Clinical Genetics and erlands; 10Department of Reproductive Health and Research, World Health EMGO Institute for Health and Care Research, Amsterdam, The Nether- Organization, Geneva, Switzerland; 11Hebrew University Jerusalem, Depart- lands; and 27Centre for Comparative , Murdoch University, and ment of Community Genetics, Public Health services, Ministry of Health, Edith Cowan University, Perth, Western Australia, Australia. Israel; 12Department of Genetic and Laboratory Medicine, Geneva Univer- sity Hospital, Geneva, Switzerland; 13Ge´nome Que´bec and Ecogene-21 Hanan Hamamy, MD, Department of Genetic Medicine and Development, Biobank, Chicoutimi, Quebec, Canada; 14Institute for Health Research, CMU 9180-Rue Michel-Servet 1, CH 1211 Gene`ve 4, Switzerland. E-mail: University of Bedfordshire, Bedfordshire, United Kingdom; 15Mental Health [email protected]. Section, PHC Department/Ministry of Health, Baghdad, Iraq; 16University Disclosure: The authors declare no conflict of interest. Diabetes Center, King Saud University, Riyadh, ; 17Aziziah Maternity and Children Hospital, Ministry of Health, Jeddah, Saudi Arabia; Submitted for publication January 6, 2011. 18Department of Obstetrics and Gynecology, Medical City, Baghdad, Iraq; Accepted for publication February 15, 2011. 19Hadassah University Medical Center, Jerusalem, Israel; 20King’s College, Published online ahead of print May 6, 2011. London, University of Oxford, United Kingdom; 21Child Development Cen- tre, Bradford Teaching Hospitals NHS Foundation Trust, United Kingdom; DOI: 10.1097/GIM.0b013e318217477f

Genetics IN Medicine • Volume 13, Number 9, September 2011 841 Hamamy et al. Genetics IN Medicine • Volume 13, Number 9, September 2011 ies have indicated that inbreeding depression in is their common (), so their progeny is moderate in effect and can conveniently be analyzed by study- autozygous at 1 of 16 of all loci, which is expressed as an ing the “genetic load,” i.e., the reduction in fitness due to inbreeding coefficient (F) of 0.0625.6 The mean inbreeding ␣ ϭ⌺ deleterious genes maintained in the population by in coefficient “ ” Fimi, where Fi is the inbreeding coeffi- the face of elimination by natural selection.3 Recently, however, cient of a specific category of consanguineous marriage and 3,7,9,10 healthier viable offspring was produced by inbreeding a freshly mi is the proportion of this category in the population. generated knock-out mouse line for cytochrome P450 genes. The prevalence of consanguinity and rates of first This finding indicated a possible beneficial epigenetic role in marriage can vary widely within and between populations and inbreeding, described as “inbreeding de-repression.”4 communities, depending on ethnicity, religion, culture, and ge- Novel technologies and updated perceptions in developmen- ography. Consanguineous marriages are also practiced among tal and functional genetics and genomics may be applied to emigrant communities from highly consanguineous countries investigate potential genetic advantages with inbreeding. Re- and regions, such as Pakistan, Turkey, the Maghreb, and Leb- search into the risks and benefits of consanguinity is best anon, now resident in Europe, North America, and Australia. In undertaken through collaboration between countries with high recent years, however, these marriages have been subjected to consanguinity rates and those with appropriate scientific exper- substantial criticism in a number of Western countries. tise, and the requisite technological and financial resources. In clinical genetics, a consanguineous marriage is generally Collaborations of this should lead to the identification defined as a union between two individuals related as second and characterization of many genes responsible for human cousins or closer (F Յ 0.0156)6,11 (Fig. 2), but in highly diseases, with direct benefits both to the populations investi- consanguineous populations, pedigrees with complex consan- gated and to a better understanding of the genetic bases of guinity loops are commonplace (Fig. 3), arising from close kin human health and disease worldwide.5 unions in preceding . Reports on consanguinity rates may sometimes include marriages between third cousins or COMPARATIVE GLOBAL CONSANGUINITY more distantly related individuals (F Յ 0.0039).12 Although this RATES AND PREFERRED RELATIONSHIPS discrepancy affects the total consanguinity rate, because of the lower coefficients of inbreeding in more remote unions, it does As illustrated in Figure 1, consanguineous marriage is tradi- not markedly alter the mean inbreeding coefficient (␣). tional and respected in most communities of North Africa, the Unions between individuals with at least one common an- Middle East and West Asia, a transverse belt that runs from cestor, such as those commonly occurring in religious and social Pakistan and Afghanistan in the east to Morocco in the west, isolates, villages and small towns, and within tribes, are referred and in South India, with intrafamilial unions collectively ac- to as intracommunity or endogamous marriages. The custom of counting for 20–50ϩ% of all marriages.6,7 First cousin unions endogamous marriage among individuals belonging to the same (F ϭ 0.0625) are especially popular, comprising 20–30% of all or tribe often results in an unequal distribution of founder marriages in some populations (Table 1), in particular the pa- across populations. Allelic heterogeneity for very rare ternal parallel subtype in Arab societies (Fig. 2) (On average, autosomal recessive disorders also has been observed in an first cousins share one of eight of their genes inherited from increasing number of highly consanguineous populations, with

Fig. 1. Global total consanguinity rates.6

842 © 2011 Lippincott Williams & Wilkins Genetics IN Medicine • Volume 13, Number 9, September 2011 Geneva Consanguinity Workshop Report

consanguineous, with 20ϩ% between and their nieces Table 1 Percentages of first cousin and closer marriages ϭ 17 Ն (F 0.125). (F 0.0625) by country in representative Close kin marriage can be a strategy of conservation, with 6,8 consanguineous populations providing excellent opportunities for the trans- 18 Country First cousin and closer marriages (%) mission of cultural values and cultural continuity. For these reasons, consanguineous unions are generally thought to be Afghanistan 25–30 more stable than marriages between nonrelatives, although the Bahrain 8–26 data so far available on marital discord and are small in number. In most Arab societies, patrilateral parallel cousin Egypt 14–24 marriages are regarded as important in uniting members of the India (south)a 7–42 same descent group and keeping the education of offspring within the line. These considerations may be particularly Iran 6–26 significant under conditions of social change and political or 19 Iraq 29–33 socioeconomic insecurity. Thus, higher rates of close kin marriage have been observed among certain minority ethnic Jordan 19–39 groups, especially during the initial phases of settlement of 20 Kuwait 17–31 emigrant communities and refugees. Conversely, in South India and according to Confucian in China, although Lebanon 7–31 marriage between a man and his ’s ’s is Libya 25–30 permitted, patrilateral parallel cousin unions are viewed as incestuous.11 Morocco 9–10 Oman 24–34 SECULAR AND SOCIAL TRENDS IN Pakistan 17–38 CONSANGUINEOUS MARRIAGE Palestinians 14–34 The probability of consanguineous marriage is thought to be Qatar 27–35 determined by such factors as the availability of consanguine- Saudi Arabia 25–42 ous kin of comparable age, the similarity of socioeconomic conditions and physical traits among relatives, and for Sudan 44–49 or against specific types of consanguineous marriages.3 In many Syria 12–50 societies, more distant consanguinity (i.e., beyond second cous- ins, F Ͻ 0.0156) often arose while people were living in small Tunisia 18–23 rural communities. Although remote levels of consanguinity Turkey 15–25 seem not to have a major adverse impact on health, because of multiple inbreeding loops, they can result in a notable increase United Arab Emirates 20–30 in homozygosity. This trend was, however, broken in Western Yemen 32–34 societies due to increasing urbanization after industrialization in the 19th century and in the aftermath of the World Wars of the Rates can differ within the same country depending on choice of subjects and 21 methods used. 20th century. aPredominantly -niece marriages (F ϭ 0.125). Significant secular changes in consanguinity rates have been reported in recent decades. In Jordan,9 Lebanon,22 and among Palestinians,19 the decrease in the frequency of consanguineous marriage could be attributed to a number of factors, including higher levels of female education, declining fecundity with the coexistence of multiple mutations encoding specific inher- lower numbers of marriageable relatives, increased rural to ited disorders in Middle Eastern Arab, Jewish, and Druze com- urban mobility, and the improved economic status of . munities, findings that have been ascribed to random mutational Moreover, public health concerns centered on the role of genetic events and/or selective heterozygote advantage.13,14 diseases as causes of severe morbidity and mortality are likely to increase with the declining prevalence of infectious diseases. CONSANGUINITY AND SOCIAL STRUCTURE On the other hand, social, religious, cultural, political, and economic factors still play important roles in favoring consan- Sociocultural factors, such as the maintenance of family guineous marriages among the new generations. This is partic- structure and property, ease of marital arrangements, better ularly the case in rural areas17,23 and to an extent among highly relationships with in-laws, and financial advantages relating to educated males but less frequently in tertiary educated fe- , seem to be strong contributory factors in the preference males.10 In fact, consanguinity seems to be increasing in some for consanguineous unions. In addition, there is a general belief Arab countries including Qatar24 and Yemen,25 possibly be- that marrying within the family reduces the possibilities of cause of a belief that the social benefits of consanguineous hidden uncertainties in health and financial issues.11 Contrary to marriages can outweigh the genetic risks and also because of common opinion, consanguinity is not confined to Muslim misconceptions surrounding the nature of genetic risks among communities. Many other religious groups, including the Leb- some members of the general public. However, variability in the anese, Jordanian, and Palestinian Christian populations, also composition of the populations sampled across generations practice consanguineous marriage, although to a lesser extent make such observations difficult to confirm. than among coresident Muslims,10,15,16 whereas in the Hindu The prevalence of consanguinity markedly declined in Eu- population of South India, more than 30% of marriages are rope, North America, and Japan in the last century,26,27 with a

Genetics IN Medicine • Volume 13, Number 9, September 2011 843 Hamamy et al. Genetics IN Medicine • Volume 13, Number 9, September 2011

Fig. 2. Categories of consanguineous marriages.

Fig. 3. Complex pedigree illustrating multiple consanguineous marriages.

844 © 2011 Lippincott Williams & Wilkins Genetics IN Medicine • Volume 13, Number 9, September 2011 Geneva Consanguinity Workshop Report more recent reduction among some emigrant populations in Down syndrome has been reported, and, for example, in an Europe. For example, in the Norwegian Pakistani community, Arab village in Israel, multigenerational cases of Down syn- the proportion of women consanguineously related to their drome within a single endogamous kindred could not be ex- partner decreased from 45.5% in 1995–1997 to 27.3% in 2002– plained by advanced maternal age alone.33 2005 for those born in Pakistan, and from 48.3 to 18.8% among women of Pakistani origin born in Norway.28 This trend may be explained by acculturation of the immigrant community, with a QUANTITATIVE TRAITS AND COMPLEX gradual transition from their traditional consanguineous mar- DISORDERS: IS CONSANGUINITY A riage preferences to those favored by the dominant group in DETERMINANT? their adopted country.29 Most quantitative traits, such as height, skin and eye color, intelligence, and blood pressure, fall under the umbrella of HEALTH IMPACT OF CONSANGUINITY multifactorial , with both genetic and environmental factors contributing to the trait etiology in varying proportions. Consanguinity does not seem to be associated with elevated The association of parental consanguinity with such traits is rates of miscarriages, as a large majority of studies have failed vague, with few published reports that have consistently con- to detect any significant increase in fetal loss rates among trolled for nongenetic variables. consanguineous couples.8 A meta-analysis of stillbirths showed Complex disorders such as hypertension, coronary artery a mean excess 1.5% deaths among first cousin progeny, al- disease, diabetes, schizophrenia, autism, and cancer are also though data from three communities resident in a single study etiologically heterogeneous, with multifactorial inheritance sus- site were identified as significant outliers that raised the overall pected in most families and individual cases. High susceptibility mean value.30 genes could play a significant role in the expression of a In a meta-analysis of the fertility of first cousin and noncon- complex disease, and if such genes are rare and transmitted in sanguineous couples, first cousins had a higher mean number of an autosomal recessive manner, then consanguinity could be a live births in 33 of the 40 studies, which translated into a mean Ϫ determining factor.7 To date, little has been published on the 0.08 additional births per family (r2 ϭ 0.67, P Ͻ 10 9).30 effects of consanguinity on the complex late-onset disorders However, multinational studies among first cousin offspring that account for most of the global public health burden.7 The also indicated a mean 1.1% excess in infant deaths (r2 ϭ 0.61, ϫ association of consanguinity with complex disorders can be P Ͻ 10 5) compared with nonconsanguineous progeny,30 with studied using different approaches. For example, epidemiolog- an equivalent excess of 3.5% in overall prereproductive mor- Ϫ ical surveys could compare the frequency of a disorder in the tality (r2 ϭ 0.70, P Ͻ 10 5).7 Currently, it is unclear whether progeny of first cousin with that of unrelated parents, the apparent greater fertility of first cousin couples represents whereas case-control studies could compare the rates of first compensation for their increased risk of postnatal losses or may cousins among affected individuals and controls. primarily be due to their younger mean age at marriage, earlier Highly consanguineous populations provide a unique oppor- first pregnancy, and longer reproductive span.8,11,29 tunity to detect recessively inherited genes for diseases mani- The prevalence of congenital anomalies in the offspring of festing in late life, such as a study identifying multiple loci for first cousin marriages has been estimated to be 1.7–2.8% higher Alzheimer disease in an Israeli Arab community.45 than the background population risk, mostly attributable to Investigators share the difficulty of adequately defining controls, especially as autosomal recessive diseases.8,31–33 An increased 2% risk that most complex disorders are late onset in nature, and there also first cousin couples will bear a with an autosomal reces- is the difficulty of controlling for community endogamy, with sive disorder indicates that approximately 8% of these couples no guarantee that cases and controls belong to the same sub- have an increased risk of 25% or more, whereas 92% of first population. Perhaps for these reasons, association studies on cousin couples will not be at increased risk of the birth of an consanguinity and breast cancer, and the frequency of BRCA1 affected child (If the additional risk is less or more than 2%, the and BRCA2 in highly consanguineous populations, have so far 8 and 92 percentages will change accordingly.34 Rare and novel produced contradictory opinions.46,47 autosomal recessive disorders have been widely reported from Some studies have reported higher rates of specific complex communities with high consanguinity rates,35–42 as the main impact of consanguinity is the increased expression of rare disorders among consanguineous progeny, e.g., a small but signif- icant increase in the rate of cousin marriages among the parents of autosomal recessive genetic disorders. 48 The association of consanguinity with major congenital mal- Bedouin Arab schizophrenia patients in southern Israel. Simi- formations, including nonsyndromic neural tube defects and larly, in a religious isolate in The Netherlands, familial aggregation cleft lip and/or palate remains controversial. However, after of several complex disorders, including ischemic stroke, was controlling for confounders, there was a significantly increased noted. Small effective population sizes and a high cumulative level risk of specific congenital heart defects in first cousin off- of consanguinity make such populations valuable for locating and identifying novel genes, and incipient problems of ensuring rigor- spring.43 This association could variously suggest a recessive ous matching of cases and controls are easier to control.49 mode of inheritance, some effect on noncoding regulatory How- DNA, or the contribution of an epigenetic mechanism to con- ever, in most populations, unambiguous evidence-based conclu- genital heart defects. Nevertheless, in South India, where uncle- sions have been difficult to establish. niece and first cousin marriages are strongly favored,16 a ge- nome-wide linkage analysis using high-density oligonucleotide PROSPECTS FOR GENETIC RESEARCH ON microarrays was unable to identify a single gene of major effect CONSANGUINITY in a clinically heterogeneous sample of cases born to consan- guineous parents.44 Discovery of the functional genomic elements that harbor Most of the literature on the effects of parental consanguinity pathogenic mutations is a major step toward a mechanistic on Down syndrome has concluded that no such association understanding of the physiopathology of the phenotype and exists. However, in some populations, an elevated frequency of provides targets for therapeutic interventions. The technological

Genetics IN Medicine • Volume 13, Number 9, September 2011 845 Hamamy et al. Genetics IN Medicine • Volume 13, Number 9, September 2011 advances in rapid high-throughput genome sequencing and for complex adult-onset diseases are vague and inconsistent, sug- the identification of copy number variants by comparative gesting the importance of implementing future research in this genomic hybridization, therefore, offer unprecedented opportu- area. The group highlighted the importance of present-day ro- nities to identify a large number of additional links between bust molecular tools in conducting consanguinity research to genotypes and phenotypes in consanguineous families. better define genotype-phenotype correlations and assess the In the past, epidemiological studies based on consanguinity genetic risks and benefits of consanguinity. The presumptive could approximately estimate the prevalence of autosomal re- social benefits of consanguineous marriages need to be con- cessive disorders in a community. Today, new approaches for firmed by evidence-based research. estimating the frequency of autosomal recessive disorders can The efforts from the scientific community should be more use molecular characterization of mutations in the affected geared to understanding the balance between the risks and offspring of consanguineous couples. The rationale of this new benefits of consanguinity. This will help to define issues that are approach is based on a comparison of the frequency of identical of greatest relevance to people in different lifestyle situations, or nonidentical mutations in children born to consanguineous whether there are situations which justify the discouragement, parents. In the latter situation, as two mutated are not or possibly even the encouragement of consanguineous mar- identical by descent (IBD), they must have been inherited riages and, if so, how best this advice might be given. through two different ancestors of the consanguineous parents, or one is a de novo mutation. ACKNOWLEDGMENTS A positive correlation has been postulated between the fre- quency of affected individuals in whom the alleles were not Contributors: H.H. drafted the report, A.H.B. drafted succes- IBD and the frequency of pathologic alleles (q).50 The popula- sive versions, and all other contributors revised the report and tion prevalence of autosomal recessive diseases can be inferred gave final approval for publication. All contributors actively using an equation that incorporates the frequencies of the mu- participated in the workshop. tant alleles and the coefficient of inbreeding (F) (unpublished data), with the results integrated into Locus-Specific Data Bases REFERENCES that have been rapidly increasing in number during the last 1. Geneva International Consanguinity Workshop, 2010. Available at: http:// decade.51 Novel research in consanguineous families should www.medecine.unige.ch/consanguinity/. Accessed December 1, 2010. similarly focus on the proportion of DNA that is IBD in the 2. Biemont C. Inbreeding effects in the epigenetic era. Nat Rev Genet 2010; 11:234. parents of affected children compared with the parents of 3. Cavalli-Sforza LL, Moroni A, Zei G. Consanguinity, inbreeding and genetic healthy children. Data of this nature potentially could provide drift in Italy. Monographs in population biology 39. 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