Annotation

Consanguineous marriage and childhood health

AH Bittles, Centre for Human Genetics, Edith Cowan University, Perth, Australia. Correspondence to author at Centre for Human Genetics, Edith Cowan University, 100 Joondalup Drive, Perth 6027, Australia. E-mail: a.bittles@ecu.edu.au

As previously described,1 the subject of consanguineous marriage became a source of major scientic and public interest in the UK and the USA from the mid-19th century onwards. Much of this interest centred on the claimed deleterious outcomes of consanguinity, although there were also scientists and clinicians who denied any adverse effects and instead argued that inbreeding offered major biological advantages. A large majority of studies have indicated that early mortality is increased in the progeny of consanguineous unions when compared with children born to unrelated parents.2 However, most of these studies failed to control for the potential effects of sociodemographic variables. Where such control was attempted, as in extensive post-World War II surveys conducted in Japan, the adverse biological effects of consanguinity were still present but were much less obvious,3,4 and similar ndings have been reported in more recent studies in the Indian sub-continent.5,6 Particular interpretative problems may be encountered with retrospective data. As illustrated in Figure 1a, based on data collected in Japan between 1929 and 1962,7 mean cumulative mortality from birth to age 6 years was much higher in the progeny of couples who were rst cousins (99 per 1000 live births) than in the children of non-consanguineous parents (64 per 1000 live births). When the data were replotted by years of birth, however, a very different picture emerged with a marked reduction in the differential between mortality in rstcousin and non-consanguineous progeny. This is illustrated in Figure 1b which shows deaths in the rst year of life. Indeed, in the latest time period (1961 to 1962), infant deaths among rst cousin and non-consanguineous progeny were the same (48 per 1000 births). A change of this nature in infant mortality rates within just 33 years would be very difcult to explain in generational terms, and in the absence of persuasive supporting evidence a more credible explanation is that demographic and socioeconomic variables exerted a greater adverse effect on mortality in the earlier time periods. The aims of this annotation are to review briey the current global prevalence of consanguineous marriage and to estimate and describe the deleterious outcomes expressed in the early years of life. Current distribution of consanguineous marriage In clinical genetics a consanguineous marriage is most com-

monly dened as a union between a couple related as second cousins or closer, equivalent to a coefcient of inbreeding (F) in their progeny of 0.0156. That is, the parental couple share 1/32 of their genes inherited from a common ancestor(s), and on average their children have identical gene copies at 1/64 of all loci. Using this denition, human populations can be subdivided into several major groupings: societies in which fewer than 1% of marriages are consanguineous, as in Western Europe, North America, Australasia, and Russia; or where 1 to 10% of all marriages presently are consanguineous such as the Iberian peninsula, Japan, and South America; and the majority of North and sub-Saharan Africa, West, Central and South Asia, where 20 to 50%+ of current marriages are consanguineous.8 There is no reliable information on consanguineous marriage for over 20% of the worlds population, including many of the more populous countries in Asia and Africa. Using Indonesia as an example, a review of anthropological sources indicated that rst- or second-cousin marriages were preferred or permissible in 12 of 17 different subpopulations studied.9 Thus it seems likely that a sizeable but unknown proportion of current marriages in Indonesia have been contracted between spouses who are biological relatives, and a similar situation may exist in many other countries where data are so far unavailable. In most countries the positive or negative attitudes towards consanguineous marriage reect long-standing religious or cultural beliefs. First-cousin unions (F=0.0625) are the most prevalent form of consanguineous marriage, and they are generally sanctioned within Buddhism, Confucianism, Judaism, Islam, and the Zoroastrian/Parsi religion.10 Attitudes in Hinduism are divided, with Dravidian South Indians regarding consanguineous marriage as preferential whereas in North India close kin marriage is prohibited under the Aryan tradition.11 Similar conicting attitudes and opinions exist in Christianity. Diocesan dispensation is required by the Roman Catholic Church for rst-cousin marriages, the degree of proscription is even more rigorous in the Orthodox Church, while there usually is no bar to rst-cousin unions in the Protestant denominations.10 Religion and traditional beliefs can also determine the specic types of consanguineous marriage that are permissible, and so in Arab Muslim communities rst-cousin unions between a man and his fathers brothers daughter

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are preferred, as opposed to the mothers brothers daughter pattern of rst-cousin marriage prescribed by the Hindu populations of South India.12 Social and economic considerations are important in the preference for consanguineous marriage.1214 In social terms, consanguineous marriage is believed to strengthen family ties and at the same time help to avoid health or nancial uncertainties that may arise through marriage with a spouse from another family or community. Consanguineous unions also greatly simplify premarital arrangements and the relationship of the bride and her in-laws (and relatives by birth) is predictably closer and more congenial. In countries where either dowry (payment from the brides family to the groom) or bride-wealth (payment from the groom to the brides family) is the norm, a marriage arranged within the family is an effective means of minimizing the nancial costs. A side-effect is younger female and male age at marriage and at rst birth, which is likely to increase family sizes and hence the likelihood that a recessive disorder will be expressed.15,16 In the early 20th century, consanguineous marriage in Western countries was generally rare and largely restricted to remote and underpopulated rural areas, and to religious isolates such as the Amish, Hutterites, and Mennonites in the USA.1 However, as a result of the large-scale migration from less developed countries to Western Europe, North America, and Australasia during the last 50 years, many permanent migrant communities have been established in which consanguineous marriage is regarded as the norm. For example, in the UK Pakistani community of 0.5 to 0.6 million, an estimated 50 to 60%+ of marriages are consanguineous with evidence that their prevalence is increasing,17,18 and a similar trend to increasing consanguinity has been reported among Moroccan and Turkish migrants in Belgium.19 At the same time, legislation on the accepted degrees of genetic relationship has been revised in some countries, and subject to government approval, half-siblings (F=0.125) can marry under the 1987 Swedish Marriage Law. It is thus important for neonatologists

and paediatricians to be aware of the possibility that their patients may be born to biologically related parents and to be conversant with the circumstances and outcomes of such unions. Clinical outcomes of consanguineous marriage in childhood
CONSANGUINITY AND PRENATAL LOSSES

Despite the widespread and erroneous belief that fertility is reduced in consanguineous unions,20 lower levels of pathological sterility have been reported in rst-cousin progeny.214 Data on foetal losses and stillbirths have been contradictory, with most studies indicating no consanguinity-associated effect15,2430 but also some reports of increased losses.4,31,32 All of these studies need to be treated with some degree of caution as they are based on mothers recall which may be unreliable,33 and by comparison with studies using serum or urinary human chorionic gonadotrophin estimations34 the levels of prenatal losses recorded are questionably low. Data on the relation between consanguinity and birth measurements have also been mixed, with a number of surveys suggesting that babies born to consanguineous parents were smaller and lighter,3539 whereas other studies failed to detect a signicant difference.403 Several caveats apply. In many of the above examples the sample sizes were small, and the majority of studies incorporated little or no control for variables such as maternal age or parity. The consanguineous couples surveyed may also have been born to parents who themselves were descended from generations of intrafamilial marriages, and so their progeny would actually have a value for F>0.0625.33 Of particular importance from a community genetic perspective is the fact that the comparisons were mostly made on a straightforward consanguineous versus non-consanguineous basis with no attempt to identify or discriminate between couples from different subpopulations. As will be discussed later, this may be a serious aw, especially in a country like India where caste subdivisions, and hence multiple genetic subdivisions, have

120 100 Mortality per 1000 Mortality per 1000 80 60 40 20 0 0 1 2 3 Years after birth 4 5 6

120 100 80 60 40 20 0
1929-35 1936-40 1941-45 1946-50 1951-55 1956-60 1961-62

Years of birth

Figure 1a: Cumulative mortality, 06 years, among N , rst-cousin and L, non-consanguineous progeny in Japan (Yamaguchi et al. 1970). Figure reproduced with permission of the American Society for Human Genetics.

Figure 1b: Changing mortality proles of N , rst-cousin and L, non-consanguineous progeny in Japan, 19291962, deaths in rst year of life (Yamaguchi et al. 1970). Figure reproduced with permission of the American Society for Human Genetics.

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probably existed for up to 3000 years, with some 50 000 to 60 000 separate communities in the total population of over 1000 million.44
CONSANGUINITY AND EARLY MORTALITY

Although almost all studies based on adequate sample sizes have shown that early postnatal mortality is higher in the progeny of consanguineous unions, there has been a substantial downward revision in the estimates of excess consanguinity-associated mortality through time.27 This reappraisal probably results from better sampling techniques and, as suggested by Figures 1a and 1b, recognition that earlier surveys produced spuriously high values due to inadequate control for non-genetic variables. The most recent representative mortality estimate, based on a multi-national study of over 600000 pregnancies and live births, is that deaths from approximately the sixth month of pregnancy to a median age of 10 years are 4.4% higher in rst-cousin progeny than among the offspring of non-consanguineous unions.45 But even this gure may be somewhat exaggerated as few of the constituent surveys in the analysis had explicitly included control for potential confounding sociodemographic factors. Most studies into the outcomes of consanguineous marriage have been conducted in developing countries, with consanguinity-associated deaths largely concentrated during the first year of life.30,468 In a majority of cases no specic cause of death was identied because of poor diagnostic facilities and/or parental reluctance to sanction prenatal diagnosis or autopsy examinations. Multiple deaths also have been reported in specic consanguineous families from developing and developed countries, in proportion to the level of parental genetic relatedness.16,49 Where a child dies early in life there is convincing evidence that it is rapidly replaced.20,50 Thus reproductive compensation for a child who died of an autosomal disease generally serves to increase the number of births in a family. It also restricts the elimination of lethal recessive alleles from the gene pool as, by denition, twothirds of the surviving replacement progeny would be expected to be heterozygotes for the disease in question.
CONSANGUINITY AND MORBIDITY

be increased in frequency in consanguineous offspring,7985 and in the UK Pakistani population elevated rates of cerebral palsy have been reported,86 with the causative recessive genes mapped on chromosomes 2q24-2587 and 9p12-q12.88 Besides elevated levels of - and -thalassaemia,89,90 rare complex haemoglobinopathies involving both - and -chain mutations in the same family,91 and other haematological disorders including coagulation deciencies,92 have been reported at increased prevalence in consanguineous progeny. There also are elevated levels of acute lymphocytic leukaemia93 and childhood cancers94 in some communities, and a wide range of inborn errors of metabolism have been diagnosed in different indigenous9598 and migrant populations,60,99101 including usually rare lysosomal storage disorders102 and cerebral lipidoses.103 Discussion 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 total gene pool.2 For this reason, during the last decade many rare disease genes have been identied and their chromosomal locations mapped by studying highly inbred families with multiple affected members (e.g.6769,87,88). As previously discussed, in various regions of the world and in migrant communities which originated in these regions, populations typically are subdivided into endogamous groupings that through time have evolved into distinctive breeding pools. Founder effect and genetic drift can exert a signicant inuence on the distribution patterns of specic mutations, especially where the subpopulation is small. As a result, even in the absence of preferential consanguineous marriage, genetic isolation may result in an increase in the frequency of community-specic inherited disorders. The presence of multiple discrete subpopulations creates substantial practical difculties in the compilation of national disease registers and the organization of screening programmes for specic genetic disorders. Conversely, once a specic mutation has been identied within a consanguineous pedigree, case ascertainment in other family members can be greatly simplied.104,105 Unfortunately life is not always quite so simple and genetic heterogeneity may persist even where a recessive disorder is known to be common within a particular inbred subpopulation, with no guarantee that all affected members are homozygous for the same mutation. This situation was exemplied in a multiply consanguineous Dutch family who were members of a religious isolate and yet had two sons with cystic brosis both of whom were compound heterozygotes for the disease.106 Similarly, four different mutations for familial Mediterranean fever were identied in 13 members of an extended consanguineous Arab Muslim family in Israel, and although all individuals had two mutated familial Mediterranean fever alleles some were affected while others were asymptomatic.107 A partial overview of the complex spectrum of inherited disease that can affect consanguineous communities has been provided by preliminary reports from the Pakistani community in the UK99,101,108 and Arab communities in Israel.53,98,109 However, it must be stressed that only very rarely would all families in these communities be at risk of a particular inherited disease, because of their quite stringent
*US usage: mental retardation.

A comprehensive listing of genetic disorders that have been diagnosed in the progeny of consanguineous couples is available at http//www.consang.net. Studies into the prevalence of birth defects are especially dependent on the diagnostic criteria employed, and in less developed countries diagnoses may overlap with, and reect late foetal and neonatal survival rates. In part, this may explain the wide variation in the excess incidence of birth defects reported for rst cousin progeny, 0.7 to 7.5% greater than in non-consanguineous couples, with the higher values recorded in more recent studies.514 Congenital defects with a complex aetiology appear to be more common in consanguineous families,3,18,30,5563 possibly reecting rare or even unique recessive mutations, and there is a greater likelihood of recurrence.64 Many single gene disorders are present at increased prevalence in consanguineous progeny, including autosomal recessive non-syndromal hearing loss,6571 blindness caused by early onset retinal dystrophies,724 childhood glaucoma,736 and anophthalmos and microphthalmos.72,77 In Saudi Arabia bilateral retinoblastoma also has been reported to be more common.78 Both mild and severe learning disability* tend to

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and long-standing patterns of social and hence genetic subdivision. It is probable that increased urbanization and the gradual shift to smaller family sizes will impose major constraints on consanguineous marriage in future generations. Paradoxically, the total burden of disease can increase signicantly as populations progress in economic terms, with successful treatment of formerly lethal genetic disorders placing an ever-increasing demand on health service provision and the resources of individual families. Although consanguineous marriage may remain culturally desirable, a major shift in the balance between the social and economic benets associated with intrafamilial marriage and adverse health outcomes is underway, especially in families carrying multiple deleterious recessive genes.2 This may additionally serve to reduce the appeal of close kin unions. In conjunction with community education programmes, new diagnostic, counselling, and treatment skills are needed. A US study has revealed a knowledge gap among medical geneticists and genetic counsellors with respect to the expected outcomes of consanguineous marriage.110 To help overcome these deciencies, comprehensive recommendations for the counselling of consanguineous couples and neonatal and childhood testing of their progeny have been estabplished.111 In Western countries the recruitment of genetic counsellors who are themselves members of an ethnic community may help to instil condence in those who consult them,112 especially in regard to their preference for consanguineous marriages. Successful implementation of these various initiatives will be dependent on community cooperation. They will not be aided by well-meaning but misconceived advice from external agencies that consanguineous, and even intracommunity marriage, simply should be avoided. Directive interventions of this nature run counter to a basic precept of genetic counselling.105 More importantly, they underestimate the central and valued role that consanguineous marriage has traditionally played in the lives of many different populations. Finally, by specically associating intrafamilial or intracommunity marriage with genetic disease, they may nullify the prospects of non-consanguineous marriage for families in which a genetic disorder is known to segregate, effectively subverting their own good intentions.
DOI: 10.1017/S001216220300104X Accepted for publication 4th April 2003. Acknowledgements The excellent technical assistance provided by Sheena Sullivan is acknowledged with gratitude. References 1. Bittles AH. (2003) The bases of Western attitudes to consanguineous marriage. Dev Med Child Neurol 45: 135138. 2. Bittles AH. (2001) Consanguinity and its relevance to clinical genetics. Clin Genet 60: 8998. 3. Schull WJ, Neel JV (1965) The Effects of Inbreeding on Japanese . Children. New York: Harper and Row. 4. Schull WJ, Neel JV (1972) The effects of parental consanguinity . and inbreeding in Hirado, Japan. V Summary and interpretation. . Am J Hum Genet 24: 425453. 5. Hussain R, Bittles AH. (1998) The prevalence and demographic characteristics of consanguineous marriages in Pakistan. J Biosoc Sci 30: 261279.

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