Consanguinity - Its Impact, Consequences and Management

The term "consanguinity" refers to relationship by descent from the same ancestor and means the amount of shared (identical) DNA. The term "consanguineous marriage" refers to unions between biologically related individuals. This chapter explores the historical, legal and religious aspects of consanguinity and discusses genetic aspects including population genetics and molecular genetics. The types of consanguineous unions allowed vary between different countries, and different religions have different traditions regarding which consanguineous unions are allowed. The main reasons for the continuation of consanguineous marriages are social and economic. People who share a recent common ancestor share more than 99.5% of their DNA; the closer the relatives are the more DNA they share. Once the relationship is between fourth cousins, the original amount of shared DNA reverts to the basic amount of 99.5%. Inbreeding is measured by the inbreeding coefficient, F, which is the probability that two genes at any locus in one individual have been inherited from a common ancestor. Many genetic diseases are recessive, meaning only people who inherit two abnormal genes for the same disease, one from each parent, will develop the disease. Since close relatives have more genes in common than unrelated individuals, there is an increased chance that parents who are closely related will carry the same disease genes and thus have an affected child.

The frequency of consanguineous marriages varies from one population to another. Consanguineous marriage is not restricted to specific religions or to population isolates, but is a long-standing practice in many regions of the world and it continues to be preferred by many populations, with more than 1,000 million people living in countries where between 20% and 50+% of marriages are consanguineous. Levels above 5% occur in the northern part of Africa, the Middle East and parts of Asia, whereas in what is described as the "Western world" – i.e. the entire North American continent, the whole of Europe (with the exception of Spain), Australia and New Zealand – the frequency is less than 1%. In South America, parts of eastern and southeast Asia, Spain and various parts of Africa the rate is between 1 and 10%. In other parts of the world the frequencies are unknown.

In the main, the detrimental health effects associated with consanguinity are caused by the expression of rare, recessive genes inherited from a common ancestor(s). The closer the biological relationship between the parents, the greater is the probability that their offspring will inherit identical copies of disease-causing recessive genes. However, in spite of all the potential health problems associated with consanguineous marriages, in the vast majority of the societies where these are common, it is generally accepted that the advantages of consanguinity outweigh the disadvantages. The rate of congenital malformations among the offspring of consanguineous marriages is approximately 2.5 times higher than that among the offspring of unrelated parents. First cousin consanguinity has been shown to be significantly associated with an increased risk of congenital heart defects, congenital hydrocephalus and neural tube defects, susceptibility to infectious diseases, underweight, and having an adverse effect on cognitive performance in some consanguineous populations. Another disadvantage is the high rate of hospitalization and utilization of the health care facilities in consanguineous communities, causing a major financial burden, much of which could be saved if the rate of consanguineous marriages were lower. However, in certain situations consanguineous marriages can actually be advantageous. The culture of consanguineous marriages and the genetics of protection against malaria may have coevolved by fostering survival against malaria through better retention of protective genes in the extended family, and also the circle of family members who can act as successful tissue donors is significantly extended. There are also many social advantages.

Offspring of consanguineous parents have an increased risk for congenital anomalies and major malformations. This is mainly due to the expression of recessive diseases, since when the parents share a common ancestor, the offspring are more likely to inherit the same variant/mutation that originated from their common ancestor. Although it is well known that offspring of consanguineous parents have an increased risk for monogenic autosomal recessive diseases, the contribution of parental consanguinity to the development of common multifactorial diseases is controversial. Most of the common diseases are multifactorial in etiology, i.e. the disease will manifest only after the risk factor level, both genetic and environmental, has exceeded a certain cut-off point. Coronary artery disease (CAD) is caused by numerous genetic and environmental factors, and a small proportion of cases are due to rare, highly penetrant variants in single genes. CAD is known to cluster in families, and early-onset CAD has a particularly strong genetic component. Hypertension is influenced by hundreds of loci, and consanguinity influences not only the blood pressure levels but also their reactivity. Asthma is primarily a multifactorial polygenic disease, although it is possible that homozygous mutations in specific genes may result in the "asthma phenotype". There are conflicting reports as to whether consanguinity plays a role in the etiology of diabetes mellitus – some studies have found an association while others have not. A possible association between consanguinity and psychiatric disorders is explored, and the possible effect of consanguinity on cancer is also discussed.

The effects of inbreeding on reproductive outcome have been extensively studied. Previously it had been considered that inbreeding contributed to increased mortality and morbidity with detrimental effects on reproductive outcome; however, some studies have shown only a moderate to slight impact. The fertility of consanguineous couples and infant and childhood morbidity and mortality in their progeny have also been extensively studied and numerous reports have concluded that consanguinity is not associated with either a significant positive or negative effect on fertility. The majority of studies found that first cousin couples produce more children. In many cases the mean number of live births to women in consanguineous marriages has been reported as being higher than that in non-consanguineous unions, although several studies found that mean fertility rates may be lower in consanguineous couples. Other reports suggested that lower fertility was possibly due to a failure to initiate pregnancy when the couple shared specific HLA haplotypes, or because of the expression of deleterious genes acting during early embryonic or fetal development that resulted in periconceptual losses. In general, higher total fertility rates have been reported in consanguineous marriages. Reports regarding the association of consanguinity and fetal wastage are conflicting, with some reporting that the total prenatal losses were essentially the same for consanguineous and non-consanguineous couples. A higher prevalence of congenital anomalies in general has been reported among first cousin couples in all populations.

Consanguineous marriages constitute over 50% of all marriages in many countries of the Middle East and Asia, and in most of these populations at least half of such unions are between first cousins. In the main, the detrimental health effects associated with consanguinity are caused by the expression of rare, recessive genes inherited from a common ancestor(s), and the closer the biological relationship between the parents, the greater is the probability that their offspring will inherit identical copies of disease-causing recessive genes. In many traditional Arab societies, in which the frequency of consanguineous marriages is very high, there is generally a low level of genetic literacy among the public and most health care providers, and therefore the need for education is of vital importance in such communities before any programs can be established that aim to reduce the rates of these marriages. The main factor in establishing educational and counseling programs aimed at reducing the frequency of consanguineous marriages is to identify the target group(s) who would benefit most from such programs. We report here several studies carried out in different countries with high rates of consanguineous marriages that aimed to assess the levels of awareness among various groups, both general public and health care professionals, regarding the health problems associated with such marriages. The information gained from these surveys was used in each case to establish educational and counseling programs geared to that specific society.

Even though most people accept that consanguinity can have a deleterious effect on the health of the offspring, the fact that such marriages have been practiced worldwide for many hundreds of years indicates that the advantages are generally perceived as greatly outweighing the disadvantages. The detrimental health effects are mainly caused by the expression of rare, recessive genes inherited from a common ancestor(s), and the closer the biological relationship between the parents, the greater is the probability that their offspring will inherit identical copies of disease-causing recessive genes. In most families where the parents are first cousins this added risk is estimated to be about 2-4% above the background risk in the general community. In recent years there has been a general overall reduction in the frequency of consanguineous marriages worldwide, although the current rates in most of the countries where they are practiced are still unacceptably high. Attempts to reduce the incidence of consanguineous marriages should be undertaken with tact and diplomacy together with an insight into and knowledge of the cultural and societal norms of the communities concerned. We describe attempts in various countries to offer training, educational and counseling programs aimed at reducing the incidence of consanguineous marriages. We also discuss whether religious intervention to discourage the practice of consanguineous marriage would be effective, and whether the participation of a Muslim cleric or physician might influence the decision-making process among women (and their husbands) with regard to their acceptance of prenatal diagnosis and termination of pregnancy.

Premarital and preconception genetic counseling are very important in highly consanguineous populations. In many traditional Arab societies, family-oriented genetic counseling offers an excellent approach in the prevention of genetic disorders. In most of the Arab countries, many of the towns and villages are, in effect, closed communities, in which the residents mainly marry within their own community. Within each town or village there can be at least one, and often more, autosomal recessive disease(s) that is/are exclusive to the residents of that specific location. Identifying the molecular basis of these diseases can enable genetic counseling and genetic screening, and therefore may greatly reduce the number of affected infants born. Methods used to identify the genes responsible for causing specific diseases include sequencing of specific genes, linkage analysis, homozygosity mapping and exome sequencing. Homozygosity mapping aims to identify the candidate region in which the causative gene is situated. Next generation sequencing techniques include exome sequencing; this focuses on only the protein-coding portion of the genome and is a powerful and costeffective method for elucidating the genetic basis of Mendelian disorders with hitherto unknown etiology. Once the causative gene for a specific disease has been identified, prenatal diagnosis by mutation testing in CVS or amniocytes can be carried out and termination of pregnancy offered in the case of an affected fetus. Preimplantation genetic diagnosis is described; this is a technique used to analyze embryos genetically before their transfer into the uterus in order to enable only unaffected embryos to be transferred.