Consanguinity and its relevance to clinical genetics

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Clin Genet 2001: 60: 89–98 Printed in Ireland. All rights reser6ed

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Consanguinity and its relevance to clinical genetics Bittles AH. Consanguinity and its relevance to clinical genetics. Clin Genet 2001: 60: 89 – 98. © Munksgaard, 2001 Marriage between close biological relatives is generally regarded with suspicion and distaste within Western society, reflecting historical and religious prejudice. By comparison, in many other populations there is a strong preference for consanguineous unions, most frequently contracted between first cousins, and marriage outside the family is perceived as a risky and disruptive option. The increasing importance of the genetic contribution to the overall disease profile in both developed and developing countries has highlighted potential problems associated with detrimental recessive gene expression in consanguineous progeny. This review examines the outcomes of consanguineous unions, with proposals as to how the ongoing preference for consanguinity in many communities can best be accommodated from a clinical genetics perspective.

The subject of close kin marriage, sometimes confusingly referred to as interbreeding, became a source of major scientific and public interest from the mid-nineteenth century onwards, with leading scientists, including Charles Darwin who had married his first cousin Emma Wedgwood, and his half-cousin Francis Galton, closely involved. The first comprehensive investigations into the effects of inbreeding in human populations commenced in the late 1940s, with the classic studies of Neel and Schull into the outcomes of cousin marriage in Hiroshima and Nagasaki, Japan (1 – 4), and followup work on the island of Hirado (5). Research into the prevalence and patterns of consanguineous marriage in South India demonstrated that the preference for close kin unions extended across religious and socioeconomic boundaries (6, 7), findings that through time were repeated in many other countries (8). These data showed that, contrary to widespread opinion in Western countries, consanguinity was not confined to religious isolates such as the Amish, Hutterites, and Samaritans, or to disadvantaged rural isolates, but was widely preferential in many major populations. More recently, these investigations have overlapped with the Human Genome and Genome Diversity Projects, and studies employing homozygosity mapping to locate disease genes in specific sub-populations. In Western countries, the

AH Bittles Centre for Human Genetics, Edith Cowan University, Perth, Australia

Key words: clinical genetics – consanguinity Corresponding author: Prof. AH Bittles, Centre for Human Genetics, Edith Cowan University, 100 Joondalup Drive, Perth WA 6027, Australia. Tel.: +61 8 94005623; fax +61 8 94005851; e-mail: [email protected] Received 2 February 2001, revised and accepted for publication 1 March 2001

large-scale migration of communities from regions where consanguineous marriage is favoured has provided an additional boost to medical and scientific interest in human inbreeding. The central aim of this review is to assess how consanguinity currently impinges on clinical genetics, and to predict future trends in the prevalence and outcomes of consanguineous marriage in the populations of developing and developed countries.

The global prevalence of consanguineous unions Geographical distribution

In clinical genetics a consanguineous marriage is most commonly defined as a union between a couple related as second cousins or closer, equivalent to a coefficient of inbreeding in their progeny of F]0.0156. Using this definition, a broad-scale map of the current distribution of consanguineous unions is shown in Fig. 1. The detailed information on which the map is based (8) also is available on the Web at, accompanied by listings of the relationship between consanguinity and birth measurements, and specific physical defects and behavioural and psychiatric disorders that have been diagnosed in consanguineous unions. Four major global areas can be defined (Table 1): regions in which fewer than 1% of marriages 89


Fig. 1. The current global prevalence of consanguineous marriage.

are consanguineous (although consanguineous unions beyond second cousins, F B 0.0156, may exist), typified by North America, most of Europe, and Australasia; regions such as the Iberian peninsula, Japan and South America in which 1 – 10% of all marriages are consanguineous; and North Africa, much of West, Central, and South Asia, where 20 to over 50% of current marriages are consanguineous. The highest levels of inbreeding recorded in major populations have been in urban Pondicherry, South India (9), where 54.9% of marriages were consanguineous, equivalent to a mean coefficient of inbreeding (a) of 0.0449, and among army families in Pakistan (10) with 77.1% consanguinity (a=0.0414). In the South Indian study, 20.2% of marriages were uncle –niece and 31.3% first cousin, whereas in Pakistan 62.5% were between first cousins. Information on consanguinity is at best partial in other populous countries, such as Indonesia, and for that reason their status with respect to consanguineous marriage has been designated as unknown. In fact, data are available indicating that cousin unions are favoured in a number of these populations, important examples being the Sotho and Tswana peoples of Southern Africa (11, 12). Thus, the overall figures cited for global levels of consanguinity are deliberately conservative. Of necessity a map of this type lacks detail, and in Western Europe it could be argued that in countries such as Finland, a cumulative history of third cousin marriages (F =0.0039) can be of clinical significance in remote communities (13), and in 90

conjunction with mutation enrichment may lead to a high prevalence of unique genetic disorders (14). Similarly, although the overall level of consanguinity in the UK is described as less than 1%, in the resident Pakistani community of some 0.5 million an estimated 50% to 60 +% of marriages are consanguineous, with evidence that their prevalence is increasing (15, 16). The influence of religion and civil legislation on consanguinity

Religion exerts a major influence on consanguinity. In general, consanguineous unions are sanctioned within Judaism, Buddhism, and in the Zoroastrian/ Parsi tradition (17). Attitudes towards consanguinity within Islam are somewhat ambiguous. While the prevalence of close-kin marriage exceeds 50% in many of the Muslim countries of the Middle East and Pakistan, there is no specific guidance in the Koran that could be interpreted as encouraging consanguinity (18). Indeed, according to one of the hadith, recorded pronouncements of the Prophet Mohammad, cousin marriages were best discourTable 1. Global prevalence of consanguineous marriage Consanguinity (%)

Numbers (million)

B1 1–10 20–50+ Unknown Global population

1 087 2 661 985 1 334 6 067

Consanguinity and its relevance to clinical genetics

aged. On the other hand, the Prophet married his daughter Fatima to Ali, his paternal first cousin and ward. Thus, for Muslims, cousin marriage could be interpreted as following the sunnah, i.e. the deeds of the Prophet. As previously noted, Dravidian South Indians regard consanguineous marriage as preferential, whereas in North India consanguinity is prohibited under the Aryan Hindu tradition, with family records consulted over an average of seven generations on the male side and five generations for females to ensure avoidance of unintentional inbreeding (19). Like Hinduism, there are conflicting attitudes and opinions in Christianity, with specific dispensation required by the Roman Catholic Church for first cousin marriages, and even more rigorous proscription in the Orthodox Church. By comparison, the Protestant denominations basically follow the Judaic guidelines laid down in Leviticus 18:7–18, with consanguineous unions up to and including first cousins permissible. First cousin marriages are permitted under civil law throughout Western Europe, and in most countries settled by European migrants, such as Australia and Canada. In many Western European countries, legislation on marriage has been undergoing reform, usually to permit a wider range of recognized marriage partners. Thus, under the 1987 Swedish Marriage Law, half-sibs (F= 0.125) can marry, albeit subject to Government approval. Marriage legislation in the USA is much more complicated, with individual state laws specifying precisely who can marry and under what circumstances. First cousin marriage is a criminal offence in eight states, and in a further 22 states it is illegal (20, 21). The situation is, however, still fluid and, for example, a bill to ban first cousin marriages was defeated in the Maryland legislature in 2000. With the exception of Wisconsin, which restricts first cousin marriage to couples in which one or both are infertile or where the female is over 55 years of age (20), it is difficult to discern any coherent biological rationale in the legislation on consanguinity. The rights of particular religious and ethnic groups are acknowledged in certain states, with uncle –niece marriages allowed in the Rhode Island Jewish community, and male Native Americans in Colorado permitted to marry their step-daughters. In Han Chinese society, there is a Confucian tradition of first cousin marriage between a male and his mother’s brother’s daughter (MBD) (22), but in 1981 legislation was passed in the People’s Republic of China to ban first cousin unions. Although the current situation is somewhat uncertain, it seems probable that a preference for first

cousin marriage continues in specific rural areas, especially among the 10 officially recognized Chinese Muslim populations which collectively number over 18 million (23 – 25). Social and economic factors associated with consanguinity

Consanguineous unions were most frequently reported within the ruling classes and land-owning families of Western societies. The global picture is quite different, with the highest rates of consanguineous marriage among poor, rural, and largely illiterate communities; although some land-owning families also favour consanguineous unions as a means of preserving the integrity of their estates (26). As it is the poorest sections of all populations who are most disadvantaged in terms of health care provision, this over-representation of poorer and less educated families among consanguineous couples creates problems in assessing the effects of consanguinity on morbidity and mortality. However, even when control is introduced for a wide range of sociodemographic variables, consanguinity remains a significant factor in determining early mortality (27, 28). The actual reasons given for the preference for consanguineous marriage are primarily social. It is believed that family ties will be strengthened, and health or financial uncertainties that may arise through marriage with a partner from another family or community are simultaneously avoided. In traditional Arab societies, marriage outside the family may be perceived as an insult by the family head (29). Furthermore, a man usually has the right to claim marriage to his father’s brother’s daughter (FBD) and must give his permission if arrangements are made for her to marry someone else (30). Premarital arrangements are greatly simplified in consanguineous unions, and the relationship of a couple with their in-laws is expected to be more congenial. Economic considerations also are important and, in countries where dowry or bridewealth payments are the norm, arranging marriage within the family minimizes or even obviates the potential financial costs (18, 26). Despite these various advantages, problems arising from marriage to a close relative have been cited in a minority of cases (18, 29), especially where there is a large age gap between spouses (31). The types of consanguineous marriage contracted

The specific patterns of consanguineous marriage favoured by different populations are held to reflect traditional customs and beliefs. For exam91


ple, first cousin unions between a man and his FBD are preferred in Arab Muslim communities (32), as opposed to the MBD pattern of first cousin marriage found in such disparate populations as Dravidian Hindus of South India (33), Han Chinese (25), and the Tuareg of North Africa (34). While the coefficient of inbreeding is the same at autosomal loci (F = 0.0625), for X-chromosome loci Fx =0 for FBD progeny but 0.125 in the offspring of MBD couples. Similarly, uncle –niece (but not aunt– nephew) unions (F =0.125) are permissible within Judaism but both are banned in the Koran, although double first cousin marriages (also F= 0.125) are allowed in Islam. Consanguinity and clinical genetics

The first structured clinical study into the biological effects of inbreeding was organized by Dr Samuel Bemiss of Louisville, Kentucky (35), with a report published in 1858 on the outcomes of unions ranging from incest (F= 0.25) to third cousin marriages. In Western medicine, an adverse pregnancy outcome in a couple known to be biological relatives often has been uncritically ascribed to the adverse effects of inbreeding. As recent migrant groups to Western countries are socially and economically disadvantaged, there have been complaints that too often health problems exhibited by these groups are simplistically blamed on consanguinity, without adequate allowance for other basic life-style factors (36, 37). Interestingly, in his original study of alkaptonuria published in 1902, Archibald Garrod had specifically cautioned against unjustified speculation into the overall health status of first cousin progeny, despite the fact that the six persons he had examined with the disorder were the offspring of first cousin unions (38). The excess risk that an autosomal recessive disorder will be expressed in the progeny of a consanguineous union is inversely proportional to the frequency of the disease allele in the gene pool. Thus in France, where the frequency of first cousin unions in the general population is less than 0.2%, 1.4% of cystic fibrosis cases were first cousin progeny, by comparison with 7.1% of cases of cystinosis and 12.5% of persons with achromatopsia (39). In families in which an autosomal recessive disorder is expressed, the affected progeny are not necessarily homozygotes. For example, in The Netherlands two brothers diagnosed with cystic fibrosis were compound heterozygotes for the disease, even though their parents were members of a religious isolate and were multiply related as second cousins, third cousins, and third cousins once removed, with F =0.0215 in the two children (40). 92

The clinical outcomes of consanguineous unions Consanguinity and prenatal losses

Despite the widespread belief that fertility is reduced in consanguineous unions, studies conducted in a wide range of populations have reported reduced levels of pathological sterility (33, 41, 42), and no evidence of an increase in fetal loss rates (43 – 47). Indirect indicators of fetal survival, such as multiple birth rates and the secondary sex ratio, also failed to show an inbreeding effect (48). Nevertheless, a very large proportion of conceptions are lost in the early weeks of pregnancy and preliminary DNA-based studies have suggested that selection may operate against embryos homozygous at early developmental loci (49). Data on the relationship between consanguinity and birth measurements have been mixed, with a number of studies suggesting that babies born to consanguineous parents are smaller and lighter (50 – 52), whereas other investigations have failed to detect a significant difference (53 –55). Unfortunately, the majority of these studies did not control for potentially important non-genetic variables, including maternal age at first birth. In many less developed countries consanguinity is associated with early marriage, earlier commencement of reproduction, and maximization of the maternal reproductive span through extended child-bearing, which together result in a larger number of live born children (56 –58). There also is convincing evidence of reproductive compensation, with infants dying at an early age rapidly replaced (5, 59). Although the relationship between consanguinity, fertility, and reproductive compensation is complicated, the net effect is a reduction in the rate at which deleterious genes are eliminated from the gene pool, thus reducing the ‘cleansing’ of the gene pool that has been associated with inbreeding. Consanguinity and pre-reproductive mortality and morbidity

Given adequate sample sizes, almost all studies that have examined post-natal mortality and morbidity have confirmed that the progeny of consanguineous unions are disadvantaged in health terms. Estimates as to the overall adverse effects of consanguinity have, however, been highly variable, with marked downward revision through time (60), probably resulting from better sampling techniques and, once again, recognition that earlier surveys may have produced spuriously high values because of inadequate control for non-genetic variables. The most recent mortality estimate, derived from a multi-national study of over 600000 preg-

Consanguinity and its relevance to clinical genetics

nancies and live births, is that first cousin progeny experience 4.4% more pre-reproductive deaths than the offspring of non-consanguineous unions (61). By definition, studies into the prevalence of birth defects are dependent on the diagnostic criteria employed and, in less developed countries, may overlap with and reflect late fetal and neonatal survival rates. In Japan, the incidence of birth defects was 0.7% higher in first cousin progeny (2); however, subsequent investigations have indicated higher levels of malformations. For example, a 26-year study based on the Medical Birth Registry of Norway reported 1.9% excess birth defects in Norwegian first cousin couples and 2.4% among Pakistani migrant couples (62), and first cousin progeny had 3.8% excess major malformations in an Arab community in Israel (63). In developing countries, excess consanguinityassociated deaths are largely concentrated during the first year of life ((47, 57, 64, 65) and Hussain et al. submitted), but in a majority of cases no specific cause of death is available because of poor diagnostic facilities, and parental reluctance to sanction prenatal diagnosis or autopsy examinations. Where a diagnosis has been possible, a clear link between consanguinity and autosomal recessive disorders was established (66–70). Multiple deaths have been reported in a proportion of consanguineous families from developing countries (56) and in migrant communities resident in developed countries (71), the effect being proportional to the level of parental genetic relatedness. More than 20 causative disease loci have been identified for autosomal recessive non-syndromal inherited hearing loss (72), most of which were initially located in consanguineous families (73). Blindness caused by early onset retinal dystrophies (74, 75) and childhood glaucoma (76) also have an increased prevalence in consanguineous communities, and bilateral retinoblastoma appears to be more common in Saudi Arabia (77). A significant excess of major congenital defects has been diagnosed in consanguineous progeny, especially disorders with a complex aetiology (4, 16, 51, 63, 78–81), with a greater likelihood of recurrence (82). Both mild and severe mental retardation likewise tends to be increased in frequency (83–87). In the UK Pakistani population, elevated rates of cerebral palsy have been reported in consanguineous progeny (88), with an autosomal recessive gene mapped to chromosome 2q24-25 identified in several consanguineous families with multiple affected offspring (89). As would be expected, when equivalent diagnostic facilities are available, similar patterns of defects are observed in migrant communities and in

the populations of their countries of origin. The widespread Arab diaspora provides a good example, with comparable disease phenotypes expressed in populations residing in the Middle East (81, 90, 91) and in overseas migrant communities (92 –94). It is important to emphasize that generalizations on the spectrum of inherited diseases associated with consanguinity can be misleading. In most Middle Eastern and North African populations, and in India and Pakistan, marriage is not simply arranged within the family, but is contracted within highly endogamous caste, biraderi, tribal, or clan boundaries. As an example of the genetic complexity associated with this pattern of sub-division, in India there are 299 different languages spoken by 4635 officially recognized ethnic communities, which in turn are composed of an estimated 50000 –60000 highly endogamous sub-populations (95). These groupings have histories dating back many centuries, with long and apparently unbroken histories of strict intra-community marriage, and in effect, they have evolved separate and unique gene pools. Thus, many of the genetic disorders that have been described are community-specific, which can simplify case ascertainment but presents a major problem in the compilation of national or even regional prevalence estimates. A prime example of this phenomenon was described among Arab families affected with late-infantile metachromatic leucodystrophy, living in a number of different villages in northern Israel (96). While the observed pattern of disease distribution might have been explained in terms of a single founder event and random drift in an outbred population, five separate mutations were identified among the inhabitants of these highly endogamous communities. Consanguinity and adulthood mortality and morbidity

This is potentially the most intriguing and challenging time period in which to study the influence of consanguinity on health, in particular whether there is an association with common adult multifactorial disorders. Yet, with the exception of increasing numbers of studies which employ homozygosity mapping to identify recessive disease loci, adult morbidity is a central feature of consanguinity that to date has received little attention. The adult progeny of consanguineous unions are over-represented in institutions caring for persons with mental retardation (97), but no clear association has been described between adult-onset behavioural and psychiatric disorders, such as schizophrenia, and consanguineous marriage (98 – 100). Although a preliminary report from Pakistan 93

Bittles Table 2. Health-based assessment of consanguinity Pre-industrial agrarian society

Economically developing society

Economically developed society

Female age at marriage (yr) Age at menarche (yr) Burden of infectious/nutritional disease Contraceptive usage Reproductive compensation

12+ 15+ High Low High

15+ 15+ Moderate Low–moderate Moderate–high

18+ 12+ Low Moderate–high Low

Burden of genetic disease Mortality Morbidity

Low Low

Low–moderate Low

Moderate Moderate–high

suggested that the prevalence of certain cancers and forms of cardiovascular disease was higher in consanguineous individuals (101), a study on the Arab population of Israel showed no inbreeding effect on the rates of common disorders including diabetes mellitus, myocardial infarction, bronchial asthma, and duodenal ulcer (102). The difficulty in assessing both of these sets of findings is that they were effectively composite studies, based on investigations conducted across series of discrete breeding populations, and with little control for sociodemographic variables. Without precise knowledge of the composition and structure of the consanguineous and non-consanguineous study groups, and appropriate matching between them, direct comparisons may be flawed and the results be of limited validity. Speculation and predictions on the future of consanguineous unions

It seems probable that increased urbanization and the gradual shift to smaller family sizes will impose demographic constraints on the prevalence of consanguineous marriage in future generations. Especially when, as previously indicated, quite specific types of union are favoured in particular societies while others are unacceptable. In this regard, uncle–niece and double first cousin unions, the closest forms of legal consanguineous marriage that are widely practised, would appear to be the most vulnerable. Changes of this type will necessarily be medium to long term in nature, and the impact will be slower in rural communities. As a result, consanguinity will be a topic of ongoing, and probably increasing, interest in clinical genetics and the related disciplines of community/public health genetics for the foreseeable future. The extent to which past events will be a reliable guide to the future outcomes of consanguineous unions is questionable, given the improvements in living standards enjoyed by virtually all popula94

tions, with concomitant declines in early mortality and increases in overall life expectancies. As summarized in Table 2, there has been a marked decline in age at menarche and more gradual increases in female age at marriage, which should help to reduce neonatal mortality and morbidity resulting from maternal gynaecological immaturity in developing countries (45, 59). But the major factor to be considered is the ongoing, global transition from the primarily ‘environmental’ pattern of disease of pre-industrial and modern-day economically developing societies, to the increased proportions of deaths and disability with a genetic aetiology characteristic of developed countries. Therefore, straightforward extrapolations from retrospective data collected in the Indian sub-continent will probably be of limited value in, for example, predicting the outcomes of consanguineous marriage among the UK Pakistani population, or any similar resident migrant community in a Western country. Paradoxically, the total burden of disease can grow substantially as populations progress in economic terms, with sub-lethal genetic disorders placing an ever-increasing demand on health service provision and stretching the resources of individual families. Under these circumstances, although consanguineous marriage may remain culturally desirable, there is a major shift in the balance between the social and economic benefits associated with intra-familial marriage and adverse health outcomes, especially where multiple deleterious recessive genes segregate within families (15, 103, 104). This trend is apparent in many oil-rich Middle Eastern countries, with previously undiagnosed genetic disorders revealed that had been sequestered within tribes and clans by multiple generations of strictly endogamous and intra-familial marriage ((93), and, consanguinity and physical defects). The potential scale of the problem has been further demonstrated in a highly endogamous Arab Muslim set-

Consanguinity and its relevance to clinical genetics

tlement in Israel, with 13 autosomal disorders identified and a further six possible recessive diseases under investigation (105). Major disease profile changes of this type require new diagnostic, counselling and treatment skills. Unfortunately, in many of the developing countries where consanguineous marriages are common these skills are unavailable, and there is an urgent need for training programmes to meet the existing demand (106). Complementary basic public education programmes should also be accorded high priority, given the limited understanding of genetically determined diseases in many traditional communities (18, 32, 107 –110). The large-scale emigration of individuals, families, and communities from developing countries has exposed serious knowledge gaps among health professionals in Western countries. This was evidenced by a survey conducted among medical geneticists and genetic counsellors in the USA, with estimated risk rates for birth defects and mental retardation in first cousin progeny ranging from 0.25 to 20% (111). To help overcome these deficiencies in a practical manner, comprehensive recommendations for the counselling of consanguineous couples and neonatal and childhood testing of their progeny have since been drawn up (Bennett et al., submitted). Additional problems encountered with some migrant families have included late reporting for prenatal examinations (112), and poor attendance at genetic clinics (113), which in part has been solved by the recruitment of counsellors from different ethnic groups (15, 112, 113). Counsellors who are members of an ethnic community not only help to instil confidence in consultands, they also have a clearer appreciation why consanguineous marriages are valued and at the same time are more conversant with the often complex modes of inheritance encountered (36, 103, 112, 114). The good news is that with improved knowledge of the patterns of disease inheritance in specific populations and access to comprehensive databases, the nature and extent of individual community needs can be realistically appraised and appropriate treatment and prevention programmes established (106). The successful implementation of these programmes will, however, be critically dependent on community cooperation, which in turn will require non-judgemental acknowledgement of their particular social and religious beliefs by all health professionals. Acknowledgements The long-term support, advice, and constructive criticism of many colleagues are gratefully acknowledged, in particu-

lar Profs N. Appaji Rao and H.S. Savithri, and Dr. R. Hussain.

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