Consanguinity has been shown to have an effect on susceptibility to certain infectious diseases. Lyons *et al*. showed that genetic heterozygosity is a key predictor of fitness in natural populations, partly as a result of inbreeding depression, because inbred individuals have low heterozygosity [78]. They studied 148 children who died of invasive bacterial disease (bacteremia, bacterial meningitis or neonatal sepsis), and 137 age-matched healthy children in Kenya. They genotyped samples for 134 microsatellite markers and analyzed these for an association between homozygosity and mortality. They found that at five markers homozygosity was strongly associated with mortality. In another study by Lyons *et al*., the authors showed that there is a strong association between consanguinity and susceptibility to both tuberculosis and persistent hepatitis B virus infection in West Africans, indicating that consanguinity is an important risk factor in susceptibility to infectious diseases in humans [79].

### **Other Conditions**

A positive association of consanguinity with cleft lip and/or palate has been reported among Palestinians [13] and the Lebanese [80], but not in studies in Kuwait [81] and Saudi Arabia [82]. Consanguinity has also been identified as a risk factor for underweight, showing that couples who were first cousins were 1.5 times more likely to have an underweight child as compared to those couples who were not first cousins [83]. Consanguinity can also have an adverse effect on cognitive performance, which has been shown to be significantly lower in the children of consanguineous marriages [84-86].

### **BENEFICIAL EFFECTS – GENETIC AND SOCIAL**

### **Genetic**

The hypothesis has been put forward that, in contrast to the harmful effects of consanguinity, in certain situations consanguineous marriages can actually be advantageous. Denic and Nicholls suggested that in the case of the most common monogenetic conditions in humans, α-thalassemia, glucose-6-phosphate dehydrogenase (G6PD) deficiency, hemoglobin C, and Duffy antigen negative red blood cells, which have evolved under pressure from malaria, their survival and selection have been enhanced by consanguineous marriages in malaria-infested regions of the world [87]. The authors postulated that there are various reasons for this. Firstly, the presence of two mutations in homozygotes of the abovementioned conditions (except G6PD deficiency) confers better protection against malaria than the presence of one or no mutation (heterozygous or normal genotypes, respectively), and consanguinity increases the number of homozygotes, especially at low allele frequency. For G6PD deficiency, inbreeding may increase the allele frequency of the G6PD-deficient allele. Secondly, there is an overlap between the geographic distributions of malaria, thalassemias, and other red blood cell conditions that protect against malaria, and consanguineous marriages. Thirdly, the distribution of different intensities of malaria infestation matches the frequency of human inbreeding. The authors concluded that these observations taken together strongly support the hypothesis that the culture of consanguineous marriages and the genetics of protection against malaria have co-evolved by fostering survival against malaria through better retention of protective genes in the extended family [87].

Denic *et al*., in a further study on consanguinity and malaria, noted that when the mortality from malaria is low, consanguinity lowers the population with α+ thalassemia by causing an excessive number of deaths *via* recessive lethal alleles and by negligibly slowing down the selection of the α+-thalassemia allele [88]. They also found that an enhanced speed of selection of the α+-thalassemia allele in inbred populations increases the relative fitness against malaria, and commented that when mortality from malaria is high, this increase in fitness could offset the loss of life resulting from inbreeding. Therefore, they suggest, consanguinity augments the fitness of a population with endemic malaria through its effect on the α+-thalassemia allele [88].

Inbreeding depression (described above) is the reduced survival and fertility of offspring of related individuals [2]. Nebert *et al*., however, observed the opposite phenomenon, a situation they described as "inbreeding de-repression", which they defined as the beneficial effects that result from mating related individuals [89]. By inbreeding a freshly generated knockout mouse line, the authors found that subsequent generations produced much healthier viable offspring compared with the F1 generation. The authors suggested that these findings represent the action of natural selection, where only the healthiest animals survived and were able to breed the subsequent generation. Because this inbreeding de-repression phenomenon happened within just two to four generations, the authors presumed it reflected epigenetic rather than genetic changes in the genome.

Consanguinity can also result in the homozygous expression of beneficial recessive genes. Another notable advantage is that in populations with high frequencies of consanguineous marriages, the circle of family members who can be successful tissue donors is significantly extended, thus reducing reliance on sibling donors [32].

## **Social**

The fact that consanguineous marriage has been practiced for centuries worldwide indicates that the advantages of this type of union greatly outweigh the disadvantages in the societies in which it is prevalent. The main reasons for the continuation of these unions are social and economic. Factors contributing to the

### *Genetic Disorders, Malformations, Benefits Genetic Research to the Rescue!* **65**

high incidence of these marriages include a lack of suitable mates outside the family as a result of geographical, tribal or cultural isolation, so that marriage to a relative may be the only sort that is possible. Preservation of property, especially land, and the desire to keep this within the family is another important reason [33]. Other reasons include the popular belief that intrafamilial marriage offers advantages in terms of compatibility of the bride with her husband's family, where the bride herself finds it reassuring to marry into a known family background; tradition, strengthening of family ties, maintenance of family structure, a closer relationship between the wife and her in-laws, greater marital stability and durability, ease of prenuptial negotiations, enhanced female autonomy, and the desire to avoid hidden health problems and other undesirable traits in a lesserknown spouse [90]. Care for people in old age has been suggested as a reason [91], and lower domestic violence and divorce rates have also been claimed [92]. In traditional Arab societies, marriage outside the family may be perceived as an insult by the family head [93]. Furthermore, a man usually has the right to claim marriage to his father's brother's daughter. Economic considerations also are important and, in countries where dowry or bridewealth payments are the norm, arranging marriage within the family reduces or even obviates the potential financial costs [20, 94]. Dowry, according to Hussain, is the major economic transaction that determines marriage decision-making [94]. He suggests that it is generally true that the size of the dowry is a consideration in opting for cousin marriages, because the demands and expectations of the potential in-laws, who are also close relatives, are likely to be lower and more realistic. Also, and perhaps more importantly, the bride and her family are less likely to be 'penalized' for any perceived shortcomings in the expected dowry.

The family is the main source of social security for most people worldwide [91]. In communities that prefer consanguineous marriage, the close family structure offers protection for socially or medically disadvantaged members, and as a result relatively less stigma might be attached to inherited conditions. Therefore, any attempt to alter the marriage pattern on medical grounds could undermine the very support systems that help people to cope with genetic disadvantage.

Religious reasons for preferring consanguineous marriages have been cited; however, Hussain commented that the suggestion that Islam favors marriage

between close relatives other than the proscribed ones such as siblings, parent and child, uncle and niece or aunt and nephew, is, in fact, erroneous [94]. He pointed out that there are actually no passages in the Koran that can be interpreted as encouraging consanguineous marriages. Indeed, the Islamic faith discourages consanguineous marriages, and Muhammad, the prophet of Islam, in his Traditions in fact stated: "Alienate the sibling spousal" [8].

Khlat *et al*., in a survey conducted in 1984 and 1985 in Beirut among 100 women who had married relatives and a matched group of 100 women who had married non-relatives, found that some of the women in consanguineous marriages (and a few of the matched women) as adolescents were contemplating marriage to a relative [95]. The authors suggest that this indicates that the acceptance of consanguineous marriage is rooted in the system of values prevailing in the upbringing of girls. Interviewees often commented that they would rather have their son/daughter marry his/her cousin than a stranger. This attitude has to be seen in the wider context of intra-familial preference that is prevalent in the Middle East. A mother feels better about her son marrying his cousin rather than someone else because she knows her niece's personality and family background well. With a daughter the motivations are slightly different; by marrying her cousin, she is protected from any possible mistreatment to which she might be exposed in an unfamiliar setting. It is particularly important to note that "protection of the woman" was the most frequently quoted as an advantage of cousin marriage, while "economic benefits" was mentioned only twice. The favorable perception of in-laws and their greater involvement in the family life of the women who marry relatives fits well in this framework by highlighting the continuation of common family interests that existed before marriage. Thus, whereas the economic argument may have been decisive in rural situations, it is of much lesser importance in an urban setting where the family is no longer the major unit of production; there, the maintenance of family cohesion takes precedence over financial concerns [95].

Bhopal *et al*. conducted a survey between 2007 and 2010 in Bradford, a city in West Yorkshire, England, in which 20.5% of the population are Asian or Asian British, and where in one specific district 73% of the population are of South Asian origin [96]. They compared Pakistani and other ethnic groups in

### *Genetic Disorders, Malformations, Benefits Genetic Research to the Rescue!* **67**

consanguineous marriages with Pakistani, other ethnic groups (mainly Indian and Bangladeshi) and white British groups not in consanguineous relationships in order to determine whether there were any social or economic benefits associated with consanguineous marriages. A total of 11,396 pregnant women at 26-28 weeks' gestation completed a questionnaire, including questions about their relationship to their baby's father. The authors found that among the Pakistani group, 37.5% were in first-cousin marriages, 21.8% were in more distantly related marriages, and 39.2% were not related to their partner (information was missing for 1.4%). In the group of subjects from other ethnic origins, 5% were in firstcousin marriages, 2.3% were in more distantly related marriages, while 92.5% of the marriages were non-consanguineous (information was missing for 0.3%). In the white British group, 99.7% of the marriages were non-consanguineous; there were no first-cousin marriages, 0.1% more distantly related marriages, and 0.1% where information was missing. The authors determined that even though people in consanguineous relationships were generally less educated and economically less well-off than their counterparts in non-consanguineous marriages, they were not disadvantaged, and in certain cases were actually advantaged, in a wide range of other factors that were important in their lives and relevant to their health. These included financial, marital and mental well-being, such as capacity to pay bills (similar), divorce (rarer), warmth and trust in the marital relationship (similar), enjoying ordinary activities (similar) and mothers' smoking (rarer). The authors concluded by commenting that "the danger of stigmatizing and alienating ethnic minorities who practice consanguinity can be countered by public health policy that reconsiders the balance of harms and potential benefits" [96].

## **IMPACT OF CONSANGUINITY ON THE PROVISION OF MEDICAL AND GENETIC COUNSELING SERVICES**

In the last approximately 60 years there has been a significant decline in developed countries in childhood illness caused by infections and malnutrition. The widespread implementation of vaccination programs, better nutrition and the development of antibiotics to treat infectious diseases have resulted in a shift in emphasis in the provision of medical care in these countries, and nowadays a far higher proportion of all hospitalizations in childhood is for chronic and congenital diseases [33, 97]. For example, in the Israeli Arab community, approximately 16% of the children of first-cousin marriages, which account for nearly one quarter of all the marriages in this population, have major malformations [8]. This results in a high rate of hospitalization and utilization of the health care facilities in this community, causing a major financial burden, much of which could be saved if the rate of consanguineous marriages were lower.

A study by Hall *et al*. in 1973 found that 53.4% of admissions to a large general pediatric hospital in Seattle, Washington, were for diseases with a genetic component. The authors noted that patients with genetic disorders had many more admissions that were slightly more expensive, that they stayed longer in hospital, that they traveled further, and that their families paid the bill more often [97].

The 1991 population-based hospital discharge data from California and South Carolina formed the basis for a study by Yoon *et al*., which found that nearly 12% of pediatric hospitalizations in the two states combined were related to congenital anomalies and genetic diseases [98]. The children were, on average, about 3 years younger, stayed in hospital 3 days longer, incurred 184% higher charges, and had a 4.5 times greater in-hospital mortality rate than children who were hospitalized for other reasons.

McCandless *et al*. reviewed the records of 5,747 consecutive admissions (4,224 individuals), representing 98% of patients admitted in 1996 to Rainbow Babies and Children's Hospital in Cleveland, Ohio [99]. They found that 34% of admissions had a clearly genetic disorder, although an underlying disorder with a significant genetic component was present in 71% of admitted children. Disorders with a genetic determinant accounted for 81% of the total hospital charges for 1996, and the 34% of admissions with clearly genetic disorders accounted for 50% of the total hospital charges. The mean length of stay was 40% longer for individuals with an underlying disease with a genetic basis than for those without an underlying disease.

While the above papers do not specifically discuss the impact of children of consanguineous marriages, probably because in the communities studied the frequency of such marriages was negligible, by extrapolation it can be assumed that in communities where these marriages are common, the burden on the genetic services will be correspondingly greater [33]. For example, among inpatients in a large tertiary children's hospital in central Israel, the consanguineous marriage rate in the parents of Israeli Arab children with severe congenital malformations was around 50% in 2010 [100], whereas the frequency of such marriages in the general Israeli Arab population in the same year was about 29% (personal communication).

The effects of consanguinity on common diseases will be discussed in detail in chapter 4.

## **ACKNOWLEDGEMENTS**

Declared none.

## **CONFLICT OF INTEREST**

The authors confirm that this chapter contents have no conflict of interest.

### **REFERENCES**

© 2014 The Author(s). Published by Bentham Science Publisher. This is an open access chapter published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode

**CHAPTER 4**

## **Consanguinity and Susceptibility to Common Diseases**

**Hagit N. Baris1,\*, Wen-Hann Tan2,3 and Gabrielle J. Halpern4**

*1 The Genetic Institute, Rambam Health Care Campus, Haifa, Israel; 2 Division of Genetics, Boston Children's Hospital, 300 Longwood Avenue, Boston, MA 02115, USA; 3Department of Pediatrics, Harvard Medical School, 25 Shattuck Street, Boston, MA 02115, USA; 4 The Raphael Recanati Genetic Institute, Rabin Medical Center, Beilinson Hospital, Petah Tikva, 49100, Israel*

**Abstract:** 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.

**Keywords:** Congenital anomalies, consanguineous parents, major malformations, multifactorial diseases, recessive diseases.

## **INTRODUCTION**

Offspring from consanguineous relationships, *i.e.* unions between individuals who

**Lutfi A. Jaber and Gabrielle J. Halpern (Eds.) © 2014 The Author(s). Published by Bentham Science Publishers**

**\*Address correspondence to Hagit N. Baris:** The Genetic Institute, Rambam Health Care Campus, P.O. Box 9602, Haifa, 3109601, Israel; Tel: +972-4-854-2456; Fax: +972-4-854-3029; E-mail<EMAIL_ADDRESS>
are genetically related, have long been known to have an increased risk for congenital anomalies [1-5], poor growth [6], infant mortality [5, 7-9] and major malformations [10-12]. Because their parents share a common ancestor or ancestors, these offspring are more likely to inherit the same variant/mutation in one or more genes that originated from their common ancestor(s). Although the probability of the common ancestor having a mutation in any one diseaseassociated gene is extremely low, such a risk exists for each of the over 20,000 genes in the human genome. Therefore, these offspring are at an increased risk for having homozygous mutations for disease-associated genes compared to offspring of non-consanguineous parents. However, consanguineous marriages continue to be prevalent mainly because of the socioeconomic benefits such as similar cultural values and maintaining the family's wealth [13]. These marriages are particularly common in the Middle East among the Arab communities where they are practiced by both Muslims and Christians [11].

Although it has been well-established 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 such as coronary artery disease (CAD), asthma and type 2 diabetes mellitus 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. This is known as the **threshold phenomenon** [14]. For each of these conditions there are many loci in the genome that contribute to the disease and there is no single genetic test at present that can establish a person's risk for any of these diseases.

### **COMMON DISEASES AND CONSANGUINITY**

Roberts showed an increase in susceptibility to multiple sclerosis in offspring of consanguineous parents [15]. It has been suggested that consanguinity may also have an adverse effect on cognitive performance, which has been shown to be significantly lower in the children of consanguineous marriages [16-18]. However, this might be due to an undiagnosed autosomal recessive syndrome that results in MR.

The role of consanguinity in multifactorial common adult diseases has yet to be established and several studies have reported conflicting results. Jaber *et al*. investigated the effects of consanguinity on the prevalence of diabetes mellitus, myocardial infarction, bronchial asthma, and duodenal ulcer in the Israeli Arab population [19]. The consanguinity rate was 33% and there were no differences between the male and female offspring of consanguineous *versus* nonconsanguineous marriages in the prevalence of diabetes mellitus (consanguinity: 4.3% in males, 1.5% in females *vs*. non-consanguinity: 2.9% in males, 1.6% in females), myocardial infarction (2.7%, 0.03% *vs*. 2.3%, 0.03%), bronchial asthma (2.4%, 2.0% *vs*. 3.7%, 2.3%), or duodenal ulcer (7.0%, 3.0% *vs*. 7.8%, 2.9%) (the first percentage in each pair is the prevalence of the disorder in males, and the second percentage is the prevalence of the disorder in females in consanguineous *versus* non-consanguineous matings). Moreover, the overall prevalence of these diseases among Israeli Arabs was not higher than that in the Israeli Jewish population, in which the rate of consanguineous marriages is extremely low.

In their study of consanguinity and adult morbidity among outpatients presenting to the Pakistan Institute of Medical Sciences and the Nuclear Oncology and Radiotherapy Institute, Shami *et al*. also did not demonstrate an association between cardiovascular, liver, kidney, or thyroid diseases and consanguinity, but the rate of consanguinity was higher among patients with cancer, suggesting that some Pakistani adults might be at risk for specific cancers due to homozygous mutations in autosomal recessive genes [20]. However, a study of the Qatari population, in which 51% of marriages were consanguineous, found that the offspring of such marriages had a higher risk for many common diseases, including cancer, blood disorders, mental disorders, heart disease, bronchial asthma, gastrointestinal disorders, hypertension, and diabetes mellitus; the odds ratio ranged from 2.65 for heart disease (p = 0.002) to 9.23 for hypertension (p < 0.001) [13].

### **Coronary Artery Disease**

Coronary artery disease (CAD) is the leading cause of morbidity and mortality in industrialized countries. It is a multifactorial disease caused by numerous genetic and environmental factors [21]. While some of the environmental risk factors for

### **78** *Genetic Research to the Rescue! Baris et al.*

CAD can be modulated through lifestyle modifications such as diet and exercise, the genetic factors are not modifiable. A small proportion of CAD cases are due to rare, highly penetrant variants in single genes such as *ALOX5AP* [22, 23], but many instances of CAD are caused by variants in a large number of genes. Many association studies have identified multiple genomic loci associated with CAD, of which the most strongly associated is the locus on chromosome 9p21 [24-26]. However, in most patients, CAD is due to the cumulative effect of multiple susceptibility alleles (*i.e.* genetic variants) together with adverse environmental factors (the threshold phenomenon, as described above).

CAD is known to cluster in families, and early-onset CAD has a particularly strong genetic component [27]. A family history of CAD is considered a major risk factor in disease development, not only due to susceptibility genes that are inherited through the generations, but also due to shared lifestyles that may exacerbate individual susceptibility to CAD [28, 29]. Indeed, Yasar *et al*. demonstrated that a family history of CAD is the third most important risk factor for CAD in both genders aged 45 years and younger after cigarette smoking and hypercholesterolemia in men and hypercholesterolemia and hypertension in women [30].

There is conflicting evidence for the role of consanguinity in the development of CAD. As mentioned, the offspring of a consanguineous marriage are more likely to inherit the same gene variants from each of their parents, and thus are more likely to have similar "gene determined" health outcomes [31]. It is unclear whether parental consanguinity contributes to the risk for CAD, the age of onset, or both. Ismail *et al*. assessed 193 subjects between 15 and 45 years old who had their first acute myocardial infarction (MI) and 193 age, sex and neighborhood matched controls from Karachi, Pakistan [32]. They showed that environmental risk factors such as tobacco use, ghee intake, elevated blood glucose, high cholesterol, low income, and low level of education, as well as a paternal history of CAD, were associated with premature acute MI in South Asians. This was the first published study on the association between parental consanguinity and acute MI in the absence of a family history of CAD. The authors suggested that this might be a true association, or it could possibly be explained by dietary patterns that are more likely to have been shared within the family and would therefore be more pronounced in consanguineous marriages. They speculated that consanguinity may have a confounding effect on the risk factors thought to be specific to the South Asian population. Abu-Amero *et al*. also showed that enhanced inheritance of susceptibility alleles for autosomal recessive diseases increases the likelihood of developing these diseases independent of the family history [33].

Youhanna *et al*. examined the role of consanguinity in CAD in 4284 patients [34]. They found that while consanguinity itself did not increase the risk of CAD (p = 0.38), it did significantly lower the age of diagnosis (p < 0.001). The mean age at disease diagnosis was lowest – 54.8 years – in those with both a family history of CAD and consanguineous parents, compared to 62.8 years in those without any risk factors (p < 0.001).

Mani *et al*. described a family of Iranian descent with autosomal dominant early CAD, features of the metabolic syndrome (hyperlipidemia, hypertension, and diabetes), and osteoporosis [35]. They identified a missense mutation in *LRP6*, which encodes a co-receptor for WNT ligands in the Wnt signaling pathway; this mutation reduces Wnt signaling *in vitro*. The index case, whose deceased parents were affected first cousins, was homozygous for the mutation, but his clinical presentation was similar to that of the affected heterozygotes, both in presentation and age of onset.

In summary, there are studies suggesting that consanguinity decreases the age of onset of CAD although it does not influence its risk; however, there are also reports like that of Mani *et al*. [35] that do not support this. Further studies are needed to establish the role of, and relationship between, consanguinity and CAD.

## **Hypertension**

Hypertension is a common chronic disease that leads to severe morbidity and mortality through heart disease, stroke, congestive heart failure, end stage renal disease and peripheral vascular disease. In the United States, heart disease and stroke are two of the leading causes of death [36, 37]. Hypertension, like other common diseases, has complex heritability that is influenced by both environmental and genetic factors [38, 39]; however, apart from isolated

### **80** *Genetic Research to the Rescue! Baris et al.*

successes in mapping rare monogenic loci, which account for about 5% of cases of hypertension, no major progress has been made in defining the genetic basis of essential hypertension [40]. The system of blood pressure (BP) control is complex and genetically highly variable and is dependent on various factors including cardiac output, blood vessel structure, renal function, and central nervous system control [40, 41]. Support for a polygenic model for the inheritance of hypertension also derives from animal models [40].

To study the influence of gender on BP, McArdle *et al*. carried out a genome wide homozygosity by descent mapping scan of the Old Order Amish of Lancaster, PA [42]. The Amish are a closed founder population where all the members of the community have a similar lifestyle with similar environmental factors associated with high BP, such as a high fat diet and low levels of physical activity. Two genomic loci were identified as being suggestive of linkage to systolic blood pressure (SBP) and five loci to diastolic blood pressure (DBP) in either the overall or gender-specific analyses. Sex specific analysis identified linkage to a specific region of chromosome 4 in men only, and to a region on chromosome 2 where men accounted for most of the linkage. The authors concluded that their results added evidence to a sex specific genetic architecture to BP related traits [42].

Twin studies have shown that at least 50-79% of BP variation can be attributed to genetic factors [43, 44]. Hassan *et al*. in 2001 studied 135 boys aged 9-10 years in order to ascertain whether children of first cousin parents where one or both were hypertensive have a higher BP reactivity as a result of having their BP measured for the first time as compared to the offspring of first cousin parents whose BP was normal [45]. The authors found that the reaction of the offspring of first cousin hypertensive parent(s) had significantly higher systolic and diastolic BP readings than did the offspring of first cousin parents with normal BP.

In another study Rudan *et al*. examined whether recessive alleles contributed to hypertension in humans by investigating the effects of inbreeding on BP in 2760 adults from 25 villages in Croatian island isolates [46]. They found a strong linear relationship between the inbreeding coefficient (*F*) and both systolic and diastolic BP, indicating that recessive or partially recessive quantitative trait locus (QTL) alleles accounted for 10% in females and 15% in males of the total variation in BP in this population. The authors established that each village has its unique *F* and every increase in *F* of 0.01 corresponded to an increase of ~3 mm Hg in SBP and 2 mm Hg in DBP. Regression of *F* on BP indicated that at least 300-600 recessive QTL contributed to BP variability. Eight to sixteen QTL accounted for a maximum of 25% of the dominance variation, and the authors inferred from this that in the population studied, inbreeding accounted for 36% of all hypertension. The magnitude of the inbreeding effect on BP is large – equivalent to a rise of about 20 mm Hg in SBP and about 12 mm Hg in DBP in offspring of first-cousin marriages – and is consistent with the results of previous studies in other isolate populations. The population prevalence of hypertension among individuals with no known inbreeding in their recent ancestry is about 20%, similar to most outbred populations, but it increases markedly among 50-year-olds as the inbreeding coefficient rises.

These studies show that hypertension is influenced by hundreds of loci, and that consanguinity influences not only the levels of SBP and DBP but also their reactivity. Furthermore, the inbreeding coefficient has a linear effect on both SBP and DBP.

### **Asthma**

Asthma is a clinically heterogeneous group of disorders that has been defined by the National Asthma Education and Prevention Program Expert Panel of the National Heart, Lung, and Blood Institute (National Institutes of Health, USA) as a "common chronic disorder of the airways that is complex and characterized by variable and recurring symptoms, airflow obstruction, bronchial hyperresponsiveness, and an underlying inflammation" [http://www.nhlbi.nih.gov/ guidelines/asthma/]. Clinically, asthma can be diagnosed based on the presence of: (i) recurrent respiratory symptoms such as wheezing, cough, and dyspnea, and (ii) expiratory airflow obstruction that is reversible with the use of bronchodilators. Other causes of expiratory airflow obstruction and wheezing must be excluded. There is, however, no universally-accepted working definition of asthma, which has complicated attempts to identify the genes contributing to the development of this disease [47]. Nevertheless, genome-wide association studies as well as linkage studies have identified more than 40 genes that

### **82** *Genetic Research to the Rescue! Baris et al.*

contribute to the asthma phenotype. It is believed that asthma is a multifactorial polygenic condition, involving both genetic and environmental factors. The extent of contribution of each gene to the phenotype remains unknown; however, it is believed that each gene only has a small effect on the overall phenotype [48, 49].

Various authors have attempted to determine whether parental consanguinity increases the risk for the development of asthma. Shirakawa *et al*. genotyped a variant of the β-subunit of the high-affinity IgE receptor FcRIβ – Val183Leu – and showed, in a small group of patients, an association with atopy [50]. Hijazi and Haider examined the prevalence of two variants of FcRIβ – Leu 181/Leu 183 – in consanguineous and non-consanguineous families in Kuwait who had at least one asthmatic child aged between 4 and 12 years [51]. Although the authors concluded that the Ile181Leu/Val183Leu genotype was more prevalent among the offspring of consanguineous compared with non-consanguineous families, this was not statistically significant. The authors found a higher prevalence of the homozygous Ile181Leu/Val183Leu variant amongst severe asthmatic patients compared to moderate asthmatic patients (p < 0.018). Although the authors suggested that consanguinity might contribute towards the high prevalence of the FcRIβ polymorphism in the Kuwaiti families with asthma, our re-analysis of the data presented in their paper does not support this conclusion. In fact, we opine that data from this paper suggest that consanguinity does not contribute to the risk of developing asthma.

Gürkan *et al*. in 2002 studied 140 children with asthma and 96 healthy control children, aged 3-15 years, in Turkey and found that there was no difference in the rates of consanguinity between the two groups [52]. Similarly, in a study of 103 families with 140 asthmatic children and 103 families with 295 healthy nonasthmatic children in Saudi Arabia, it was found that there was no statistically significant difference in the prevalence of consanguinity between the two groups (71/140 *vs*. 163/295 respectively; p = 0.43) [53].

On the other hand, a structured face-to-face survey conducted by nurses of Qatari women attending primary health centers or gynecological or antenatal clinics in hospitals found that 189/818 women (23.1%) in consanguineous relationships had at least one offspring with asthma compared to 84/697 women (12.1%) who were not in consanguineous relationships (p < 0.001) [54]. Although two recent studies, one conducted in south India [55] and the other in Abu Dhabi (United Arab Emirates) [56], concluded that parental consanguinity increases the risk of developing asthma, methodological issues limit our ability to draw any definitive conclusions from either study.

Asthma is believed to be primarily a multifactorial polygenic disease, although it is possible that homozygous mutations in specific genes, the risk for which is increased among offspring of consanguineous relationships, may result in the "asthma phenotype".

## **Diabetes Mellitus**

There are conflicting reports as to whether consanguinity plays a role in the etiology of diabetes mellitus (DM). In a study carried out in 1947-1948, Harris investigated 1241 diabetics at the Juvenile and Adult Diabetic Clinics at King's College Hospital, London, England [57]. Each patient was asked whether his or her parents were first cousins and, if not, whether they were related in any other way. Analysis of the data showed that there was an increase in the incidence of parental consanguinity in a series of patients with diabetes in whom the disease developed in early life, but no increase in the incidence of parental consanguinity in those in whom the disease developed later in life. It was concluded that there are genetic differences between the early onset and late onset forms of the disease and that at least some, and possibly all, the early onset cases are associated with one or more recessive genes. Anokute studied 210 male patients with DM who attended the diabetes clinic at the King Khalid University Hospital in Riyadh, Saudi Arabia [58]. One of the factors he investigated was consanguinity and questions about this were included in the detailed questionnaire given to both patients and controls. He found a positive family history of diabetes in 79.5% of all consanguineous marriages compared with 21.3% of non-related marriages. The difference was highly significant (p < 0.0001). The author commented that this high level of risk could be avoided by a cultural change.

However, El-Mouzan *et al*., in a survey in Saudi Arabia in 2004-2005, found no significant association between consanguinity and type 1 DM [59].

### **84** *Genetic Research to the Rescue! Baris et al.*

One factor that should be borne in mind when considering the validity of these papers is the huge discrepancy between the percentages of consanguineous marriages. In England in 1948 there were 18 such marriages out of a total of 1241 (1.45%), whereas in Saudi Arabia in 2005, 6470 of 11554 marriages (56%) were consanguineous. Whether the very small percentage of these marriages in the English sample affects the validity of the author's conclusions is not discussed.

### **Psychiatric Disorders**

There are several studies on a possible association between consanguinity and psychiatric disorders. In a study of first-cousin marriages among the parents of a group of randomly selected patients with schizophrenic and affective disorders, Prasad found that there were a significant number of such marriages in the schizophrenic group [60].

### **Schizophrenia**

Three studies found that consanguinity rates were significantly elevated among the parents of schizophrenic patients. Dobrusin *et al*. compared the prevalence of consanguinity in the parents of Bedouin schizophrenic inpatients in a specific catchment area of southern Israel to a control group of parents of all infants born to Bedouin mothers in the same catchment area [61]. Among the schizophrenic patients, 79% of the parents were in consanguineous marriages – 51% of these were between first cousins. In the control group, 58% of parents were in consanguineous marriages, of which 40% were between first cousins. The authors suggested that this small but significant increase in the rate of consanguineous marriages among the parents of schizophrenic patients was consistent with claims that consanguinity can contribute to the risk of schizophrenia, even though it is a polygenic illness. However, the authors stated that the absence of a better matched control group limited confidence in the results.

Bener *et al*. conducted a survey in Qatar between January 2009 and December 2010 in order to examine the impact of consanguinity on the risk for developing schizophrenia and to investigate the consanguinity characteristics of the schizophrenic patients [62, 63]. The 1184 patients completed a questionnaire that included sociodemographic characteristics and genetic and other biological

factors such as obstetric complications. They also completed a diagnostic screening questionnaire consisting of six questions on the symptoms of schizophrenia. The degree of consanguinity between the patient's parents was noted. The authors found that parental consanguinity was higher among the schizophrenic patients (41.3%) than among the non-schizophrenic subjects (28.7%), and a diagnosis of schizophrenia was more frequent among the offspring of consanguineous parents than among the offspring of non-consanguineous parents. The authors concluded that consanguinity is an important risk factor for schizophrenia in Qatar.

Mansour *et al*. conducted a study among a group of schizophrenic patients in Mansoura, the capital city of Dakahlia province in the Northern Nile Delta region of Egypt, and compared these with a group of controls [64]. The patients were 75 unrelated outpatients with a clinical diagnosis of schizophrenia, and the control group consisted of 126 adults residing in the same geographic areas as the patients and in whom a history of psychosis or bipolar disorder had been excluded. In both groups available parents were also recruited. The prevalence of consanguinity was initially estimated from family history data, and this was followed by DNA analysis using short tandem repeat polymorphisms. The authors found that self reported consanguinity was significantly elevated among the patients (46.6%) compared with the controls (19.8%) (p = 0.000058) and these differences were confirmed by DNA analysis. The authors concluded that consanguinity rates were significantly elevated among schizophrenic patients in the Northern Nile Delta region of Egypt.

In contrast, a study by Ahmed concluded that consanguinity rates were not significantly elevated among the parents of schizophrenic patients [65]. He compared the rate of first-cousin marriages among the parents of schizophrenic patients with a control group in an isolated, highly inbred Sudanese community where the rate of first-cousin marriages was 44% and found that among the schizophrenic patients, 43.7% of the parents were in first-cousin marriages, whereas in the control group the corresponding figure was 44.1%. He thereby concluded that there was no significant difference.

### **Bipolar 1 Disorder**

Two studies found that consanguinity rates were elevated among bipolar 1 patients. Mansour *et al*. carried out a study to contrast the rates of consanguinity among patients with bipolar 1 disorder and controls [66]. This study was conducted in the same setting as their schizophrenia study – in Mansoura in the Dakahlia province of Egypt. The patients were unrelated outpatients in the psychiatric clinic who had received a clinical diagnosis of bipolar 1 disorder, and the controls were adults residing in the same geographic areas as the patients. The control sample included pregnant women admitted for normal delivery or their spouses, and donors at the hospital blood bank. The authors conducted two parallel studies – the first was a case-control study comprising 93 patients with bipolar 1 disorder, 90 adult controls and available parents. The consanguinity rate was estimated by using 64 DNA polymorphisms, and also from family history data ("self report"). The second study was an epidemiological survey in which a total of 1,584 individuals were screened. Self-reported consanguinity rates were obtained for identified bipolar 1 patients (n = 35) and 150 randomly selected, unaffected controls. The authors found that the self-reported consanguinity rates were elevated among bipolar 1 patients in both surveys and concluded that their studies indicated increased consanguinity among Egyptian bipolar 1 patients in the Nile delta region [66].

Mechri *et al*. conducted a study in Tunisia in order to determine the rate of consanguinity in patients with bipolar 1 disorder and to compare the clinical characteristics and the frequency of affective disorders in first and second degree relatives of probands with and without consanguinity [67]. A total of 130 patients with bipolar 1 disorder participated. The rate of consanguinity was estimated to be 28.5%, and was higher in patients with a family history of affective disorders: 34.2% *versus* 20.4% (p = 0.08). Bipolar 1 patients with consanguineous parents had a high frequency of affective episodes, which themselves were more severe, but the difference was not significant. However, the frequency of affective disorders was significantly increased in first and second degree relatives of probands with consanguineous parents. The authors concluded that consanguinity has an influence on the clinical characteristics and the frequency of affective disorders in first and second degree relatives of bipolar patients, which is consistent with recessive polygenic transmission of bipolar disorders.

Another study found differing effects of consanguinity. Saadat carried out a study in 2012 in Shiraz, Iran, to investigate the association between parental consanguineous marriages and the age at onset of bipolar disorder [68]. Out of the 195 patients in the study, 25.6% were the offspring of first-cousin parents and 15.4% were offspring of parents who were more distantly related. The authors found that among patients with early onset of bipolar disorder, the age at onset was higher for offspring of consanguineous than unrelated marriages, whereas among patients with late onset bipolar disorder the age at onset was lower for offspring of consanguineous than unrelated marriages. However, the authors found no difference between consanguineous and unrelated marriages for intermediate age of onset.

## **Cancer**

Several studies have shown that in populations with a high frequency of consanguineous marriages, there is a significant increase in the prevalence of cancer. Single nucleotide polymorphism (SNP) array data analysis has found long regions of homozygosity in genomic DNA from tumor and matched normal tissues of patients with colorectal cancer [69]. The presence of these regions may indicate consanguinity in the individual's family tree. These autozygous regions are referred to as identity-by-descent segments (for a description of homozygosity and autozygosity in offspring of consanguineous marriages, see Chapter 3).

One survey that investigated the effects of consanguinity on the incidence of cancer and other late-onset complex diseases studied individuals from genetically isolated islands in middle Dalmatia, Croatia [70]. The investigators determined that consanguinity can be a positive predictor for a number of late-onset diseases such as heart disease, stroke, and cancer. Similar observations were noted in a study in Pakistan where, on average, cancer patients were found to have a higher coefficient of inbreeding compared with the general population [20].

In a study in Wisconsin involving descendants of an Italian immigrant group, 94% of the subjects with reported adenocarcinomas (mostly colorectal) were offspring of consanguineous marriages [71]. The authors surmised that in the extended family they surveyed, the occurrence of adenocarcinoma appeared to segregate as an autosomal recessive trait and that, in some family members, consanguineous unions led to homozygosity for the deleterious gene.

The effect of consanguinity on cancer is likely to be more complex than simple Mendelian genetics, with many additional genetic components involved. Nevertheless, studying genetically isolated populations may eventually lead to the discovery of other genes that contribute to predisposition to cancer.

Examples of cancer predisposition syndromes include Nijmegen breakage syndrome, ataxia telangiectasia, Bloom syndrome and Fanconi anemia (all types), all of which are autosomal recessive diseases. *MYH*-associated polyposis is transmitted by autosomal recessive inheritance and homozygotes have a very high risk (43-100%) for colorectal cancer, compared to the general population. However, it is unclear whether heterozygotes also have an increased risk for colorectal cancer, and if so, it is not as high (OR 1.1-3). Another example is hereditary nonpolyposis colorectal cancer HNPCC (Lynch syndrome), which is transmitted by autosomal dominant inheritance and heterozygotes are at increased risk mainly for colorectal cancer, uterine cancer and other gastrointestinal malignancies in adulthood.

Lynch syndrome is caused by heterozygous germline mutations in any of the four mismatch repair genes – *MLH1, MSH2, MSH6* and *PMS2*. Offspring of couples where both spouses have Lynch syndrome have a 1:4 risk of inheriting biallelic MMR gene mutations; these cause constitutional MMR deficiency (CMMRD) syndrome, a severe recessively inherited childhood cancer syndrome with a very broad tumor spectrum including mainly hematological malignancies, brain tumors and childhood colon cancer. Café-au-lait spots are also present. The age of presentation of these patients can also extend into young adulthood. In a recent report by an international CMMRD consortium from Toronto, Canada, 23 children with CMMRD from 14 families were studied [72]. One patient, who was aged 21 at the time of diagnosis of an oligodendrioglioma, had also had gastrointestinal polyposis and diffuse large B cell lymphoma in childhood. This patient was a compound heterozygote for two mutations in *PMS2*, suggesting that

the parents were more likely to be non-consanguineous. This patient's sibling was 24 years old at the time of presentation of a glioblastoma multiforme, but he/she had also had rectal cancer and gastrointestinal polyposis in childhood. Another patient was 17 years old when he/she presented with a glioblastoma multiforme and 17.5 years old when he/she was found to have gastrointestinal polyposis. This patient was homozygous for a mutation in *PMS2*, suggesting that the parents were probably consanguineous. Eleven of the 14 families were consanguineous, but unfortunately the authors did not elaborate on the type of consanguinity in these families. Since in 11 families the mutations the patients carried were all homozygous, even though it is not stated, it is likely that these 11 families are the consanguineous ones. In the three remaining families, the patients were compound heterozygotes for two different mutations, so these families were probably not consanguineous. The authors commented that a family history of consanguinity and a history of various malignancies combined with the presence of café-au-lait spots should raise a high index of suspicion for CMMRD [72].

In another survey, five families with CMMRD who were seen in the genetics departments of one or other of two large tertiary medical centers in Israel were studied (unpublished data). Two of the families (both Ashkenazi Jewish) were not consanguineous, but the other three were. Of these families, one was of Iranian Jewish descent; the proband, who presented at the age of 22 years with colon cancer, was the daughter of healthy first-cousin parents, each of whom was found to carry a mutation in *PMS2*. In another family, Bedouin Arabs from southern Israel, the proband, who presented at the age of 46 years with colon cancer, had Lynch syndrome. His 2-year-old niece, the third child of consanguineous parents, presented with a grade IV glioma in the left parietal region; both parents were found to be carriers of a mutation in *MSH6*. In addition, two of the proband's grandchildren, a five-year-old girl and a four-and-a-half-year-old boy of consanguineous parents, developed medulloblastomas; each of their parents was also a carrier of the same *MSH6* mutation. In the fifth family in the series, the proband was the daughter of first-cousin parents of Palestinian origin. She presented at the age of 17 years with anaplastic astrocytoma and died at age 19; both parents, who were healthy, were found to carry a mutation in *PMS2*.

More studies are needed to establish the exact role of consanguinity in common diseases.

### **ACKNOWLEDGEMENTS**

The authors thank Mrs. Inbal Kedar, M.Sc., oncogenetic counselor, for her help with the section on cancer.

### **CONFLICT OF INTEREST**

The authors confirm that this chapter contents have no conflict of interest.

### **REFERENCES**

### **92** *Genetic Research to the Rescue! Baris et al.*

© 2014 The Author(s). Published by Bentham Science Publisher. This is an open access chapter published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode

# **CHAPTER 5**

## **Consanguinity and Fertility and Reproductive Issues**

**Lutfi Jaber1,2,3,\* and Gabrielle J. Halpern4**

*1 The Bridge to Peace Community Pediatric Center, Taibe, 40400, Israel; 2 Institute of Neurology, Schneider Children's Medical Center of Israel, 14 Kaplan St., Petah Tikva, 49202, Israel; 3 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel; 4 The Raphael Recanati Genetic Institute, Rabin Medical Center, Beilinson Hospital, Petah Tikva, 49100, Israel*

**Abstract:** 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.

**Keywords:** Congenital anomalies, consanguinity, fertility, fetal wastage, human leukocyte antigen, reproductive outcome.

## **INTRODUCTION**

Clinically, a consanguineous marriage means the union between couples who are

**Lutfi A. Jaber and Gabrielle J. Halpern (Eds.) © 2014 The Author(s). Published by Bentham Science Publishers**

**\*Address correspondence to Lutfi Jaber:** The Bridge to Peace Community Pediatric Center, Box 27, Taibe, 40400, Israel; Tel: +972-9-799-1727; Fax: +972-9-799-5276; E-mail<EMAIL_ADDRESS>
second cousins or more closely related [1]. This includes double first cousins, first cousins, first cousins once removed, and second cousins. Uncle-niece marriages are prohibited in Islam but are permissible in the Hindu and Jewish religions. Consanguinity may also refer to unions of individuals with at least one common ancestor, such as those occurring within population isolates, for example, the Amish in Lancaster County, Pennsylvania [2], small towns, tribes, intracommunity, or endogamous marriages, as is frequently the case among Arab Muslim communities [3].

Over the past approximately 40-50 years, simultaneously with the decline in the prevalence of infectious diseases and malnutrition due to the widespread implementation of vaccination programs, antibiotic use and better nutrition, childhood illnesses caused by genetic diseases have assumed far more significance [4].

The biological effects of consanguineous marriages have been studied extensively in almost all populations throughout the world [5-11]. Previously it had been considered that inbreeding contributed to increased mortality and morbidity with detrimental effects on reproductive outcome [5, 7, 12]. However, studies conducted in Japan and other countries many years ago showed only a moderate to slight impact [6]. It has been suggested that the adverse consequences of inbreeding may have been eliminated by the eradication of deleterious recessive genes in earlier generations [13]; however, unfortunately, not all published studies have taken into account possible sources of bias – mainly socioeconomic status, but other confounding factors as well, such as maternal age, maternal education, birth intervals and birth order [4, 5, 14-17]. These variables have been shown to have an adverse impact on infant and 5 year survival [17]. The influences of consanguinity on reproduction are shown in Table **1**.

## **CONSANGUINITY AND FERTILITY**

The association of congenital malformations and consanguinity is well known and in the main is caused by the expression of rare recessive genes inherited from a common ancestor(s) [5]. However, little is known about the effects of inbreeding on reproduction and fertility in modern human societies; the majority of the studies were carried out over 30 years ago and not much in the way of follow-up has been conducted since. It appears that biological effects are masked by socioeconomic factors, which are the major determinants of fertility [19].

**Table 1:** Reproduction and consanguinity [18]

The aspects that have been the most extensively studied are the fertility of consanguineous couples and infant and childhood morbidity and mortality in their progeny. Reports in the literature on fertility and consanguinity are contradictory [20-36]. Hussain and Bittles reviewed 21 studies performed in India and Pakistan that found substantial variations in mean fertility levels [23].

In general, higher total fertility rates have been reported in consanguineous marriages [32-47]. The majority of studies found that first cousin couples produce more children – a finding explained partly by lower parental age at marriage and partly by the ages of the parents at the birth of their first child [5, 47] (Table **1**). In addition, the time interval between the marriage and the first pregnancy is often longer in consanguineous unions, possibly due to gynecological immaturity in women who marry at a young age. Subsequent intervals between births are usually shorter, and consanguineous couples may continue to have children to comparatively advanced ages [48]. Another reason is that consanguineous couples may be less likely to use reliable methods of contraception [37]. An additional factor is "reproductive compensation", which is a compensatory mechanism for infant and childhood losses (*i.e.* the replacement of children who die at an early age) [20].

Other studies found that mean fertility rates may be lower in consanguineous couples [19, 33, 34, 37, 49-51]. Some reports suggested that lower fertility was possibly due to a failure to initiate pregnancy when the couple shared specific HLA haplotypes [52], or because of the expression of deleterious genes acting during early embryonic or fetal development that resulted in periconceptual losses [53]. Mechanisms such as greater genetic compatibility between the mother and the developing fetus in a consanguineous pregnancy may lead to reduced rates of involuntary sterility and prenatal losses [48, 54, 55]. The association of consanguinity and fertility is shown in Table **2**.

*Table 2: contd….*

### *Consanguinity, Fertility, Reproduction Genetic Research to the Rescue!* **99**

*Table 2: contd….*

\*CM = consanguineous marriage.

Numerous studies have concluded that consanguinity is not associated with either a significant positive or negative effect on fertility [20-32]. Tadmouri *et al*. [3] reported that in the **Arab population**, higher rates of both fertility and live births were found among first cousin couples as compared with among nonconsanguineous couples in Qatar [35], Kuwait [56], Saudi Arabia [57], and Tunisia [36]. In various ethnic groups in Mauritania, it was found that consanguineous couples had significantly higher averages of fertility as compared with non-consanguineous couples [45].

Khlat investigated the effects of consanguineous marriages on fertility and mortality of offspring in Beirut through a population-based health survey of 2,752 households [21]. The total number of pregnancies, live births and living children were significantly higher among consanguineous than non-consanguineous couples, and no difference was found either in fertility or mortality when allowance was made for socioeconomic status, religious affiliation and marriage duration. The lack of a significant pattern in the final analysis was attributed to the long-term practice of consanguineous marriages. A more recent study from Lebanon suggested a positive association between consanguinity and male factor infertility among 120 infertile males, indicating the important contribution of recessive genetic factors to the etiology of male infertility [51].

As is the case with studies from other parts of the world, in **India** as well there is no complete consensus concerning the effect of consanguinity on fertility. There are two conflicting opinions – firstly that consanguinity is associated with an increased fertility rate [32, 40-42], and secondly that there is no clear association [20, 29-31]. Twenty-one studies in India and Pakistan revealed that in most cases the mean number of live births reported by women in cousin marriages was higher than that in non-consanguineous unions. Notably, in 19 of the 21 studies, women in first cousin unions had a higher mean number of live births compared to women not married to a relative [23].

Bhasin and Nag evaluated the incidence of consanguinity and its effects on fertility and child survival among the Muslims of the Ladakh region of Jammu and Kashmir. They compared the study populations with other Indian Muslim population groups and found that the incidence of consanguinity was relatively low. They also reported increased fertility and a lower proportion of surviving children in consanguineous compared with non-consanguineous marriages [41].

Asha Bai *et al*. found that fertility in southern India was higher in consanguineous than in non-consanguineous marriages, but the number of living children was approximately equal in both groups because of increased child mortality in the consanguineous group (p<0.05) [32]. The frequencies of abortion and stillbirth were also approximately equal in both groups, but the frequency of congenital anomalies was significantly higher among the offspring of consanguineous parents.

Reddy *et al*. investigated the association between consanguineous marriages and fertility and mortality among offspring in 1,500 women belonging to three endogamous communities within the Chittoor District, Andhra Pradesh, India. There were 500 women from each community [33]. Overall, the consanguineous marriages were significantly more fertile than the non-consanguineous ones. The mean number of pregnancies, live births and surviving offspring was higher among consanguineous couples. On the other hand, the authors found a significant difference in the mortality rates among the offspring between consanguineous and non-consanguineous marriages when all the marriages (those of the women, the women's parents and the women's husbands' parents) were considered in all three communities. They postulated that due to inbreeding, the offspring of earlier generations may have passed on deleterious genes to later generations, resulting in problems among the offspring of the present couple [33].

Yasmin *et al*. [42] collected data on patterns of marriage, differential fertility and mortality from 211 Kotia women living in the Visakhapatnam district of Andhra Pradesh, India. Women in consanguineous marriages had a lower mean number of total conceptions, live births and living offspring (net fertility) as compared with women in non-consanguineous marriages.

In a study in Bangalore, Karnataka, in southern India, Devi *et al*. did not find any significant differences between the consanguineous and non-consanguineous groups regarding the numbers of live born or living children [30]. Verma *et al*. reported a study conducted in 1978 in which data on 1,000 mothers in the Indian district of Pondicherry were analyzed [31]. Their findings revealed that consanguinity did not affect fertility but contributed considerably to infant mortality and morbidity.

Basu studied endogamous Muslim groups in Delhi and Lucknow, India. Certain groups had a much higher incidence of parental consanguinity than others, and different varieties of inbreeding occurred among the various groups [29]. In all of the groups the fertility rate was higher in consanguineous than in nonconsanguineous marriages, although the net fertility rate was not higher.

Bittles *et al*. performed a systematic review of the literature and collated data on 30 populations resident in six countries [20]. They found a positive association between consanguinity and fertility at all levels of inbreeding, reaching statistical significance at first cousin level (p < 0.0001). Fertility in first cousin marriages was positively influenced by a number of variables, including illiteracy, earlier age at marriage and lower contraceptive uptake, but the most important factors were duration of marriage and reproductive compensation. The authors determined that in net terms, consanguinity was not associated either with a significant positive or negative effect on fertility.

In summary, most studies have shown similar or higher fertility rates among consanguineous as compared with non-consanguineous couples. This may be attributed to the younger age of women at marriage, leading to a longer maternal reproductive span, and compensation for the higher infant mortality among consanguineous couples and lower prenatal losses among non-consanguineous couples.

### **HUMAN LEUKOCYTE ANTIGEN (HLA) GENES AND PREGNANCY**

Pregnancy can be considered as an example of a successful host-parasite interaction where the type of the immune interactions changes over the lifecycle of the parasite [58]. Because of the expression of paternal genes, the fetus and placenta have always been considered to be analogous to an allograft [59]. Allograft rejection is mediated by genes of the major histocompatibility complex (MHC), which include the human leukocyte antigen (HLA) genes, but maternalfetal HLA incompatibility is not deleterious during pregnancy [60]. The placenta is not an immunologically inert barrier; maternal and fetal cells are reciprocally transported across the placenta, and a state of mutual tolerance exists between mother and fetus during normal gestation. The classic HLA antigens that are responsible for the rapid rejection of allografts in humans are not present on placental cells at the maternal-fetal interface, and, in addition, maternal-fetal incompatibility, with respect to HLA, may actually be beneficial during pregnancy.

The fetal cells that are in direct contact with maternal tissues in the pregnant uterus are the extravillous cytotrophoblasts, which invade the maternal decidua [60]. These cells do not express any HLA class II genes, which are strongly immunogenic cell-surface markers in allogeneic transplants. Class I loci *HLA-A*  and *HLA-B*, which are expressed in nearly all other nucleated cells, are not expressed in trophoblast-cell populations. However, maternal antibodies against paternally derived HLA that are inherited by the fetus are detectable in the circulation of ~20% of primigravidae and ~40% of multigravidae [61, 62]. The

### *Consanguinity, Fertility, Reproduction Genetic Research to the Rescue!* **103**

presence of anti-HLA antibodies in a significant number of healthy pregnancies has demonstrated that sensitization to paternal HLA during pregnancy is not harmful, and, on the contrary, it has been suggested that these antibodies may in fact be beneficial. Paternal minor H antigens, peptides that are presented by Class I MHC, appear to play an important role in ensuring pregnancy success and blocking of activated abortogenic NK-lineage cells. Identifying such molecules could lead to a new approach to the diagnosis and treatment of infertility and pregnancy loss [58].

Human leukocyte antigen-G (HLA-G) is a human non-classical MHC class 1b antigen. Production of HLA-G by trophoblast cells derived from the external trophectoderm layer of the blastocyst appears to be of major importance as a mechanism of tolerance because it impairs both natural killer (NK) and T cell functions [63, 64]. The expression of HLA-G in placental tissue decreases with gestational time. The activity of the enzyme nitric oxide synthase (NOS), which synthesizes the free radical nitric oxide (NO), is also higher in first trimester trophoblast and lower in third trimester. NO can affect the immune system, either directly or by interacting with other factors. The relation between NO and HLA-G has not yet been proven; however, considering the important role of NO in the immune system and the abundance of NOS in the placenta, its role in the maternofetal tolerance seems highly probable. It is possible that NO interacts with several mechanisms at the same time [64].

Indoleamine-2,3-dioxygenase (IDO) is an enzyme present in placental trophoblast that initiates the degradation of tryptophan, and is very important in maintaining maternal tolerance [64].

No pregnancies have been reported in which all of the proteins derived from *HLA-G* are absent [63]. To date, seven alternatively spliced variants of *HLA-G* have been identified, consisting of four membrane-bound and three soluble isoforms [65].

NK cells are large granular lymphocytes whose function is the direct killing of virus-infected cells and production of cytokines, which are small cell-signaling protein molecules used extensively in intercellular communication [59, 66]. NK cells thus provide a rapid but relatively nonspecific response to infection, and, in addition, they also appear to play a role in immune surveillance against the development of metastatic spread of certain tumors [66].

It has been found that NK cells are present in abundance in the uterus at the time of implantation, and it has been suggested that they may play a role in the implantation process and the subsequent orderly growth and development of the placenta. The number and activity of NK cells appear to be altered in women with reproductive failure, although it is unclear whether the difference is a cause or effect of reproductive failure [66]. It is possible that maternal allo-recognition may be mediated by the interaction of uterine NK cells with unusual trophoblast MHC class 1 molecules [59].

Ober *et al*. studied the records of the Hutterite community [67, 68]. The Hutterites are Anabaptists who originated in the Tyrolean Alps in the 1500s. Approximately 400 Hutterites migrated to the United States in the 1870s and established three colonies in what is now South Dakota. As a result of rapid population growth, today there are more than 30,000 contemporary Hutterites living in about 300 colonies in the northern United States and western Canada. Virtually all are descendants of the founding population, who were themselves descendants of less than 90 independent genomes [69]. The average relatedness between spouses in the population studied (>1000 individuals) was greater than that of first cousins once removed (kinship coefficient = 0.0369). Because of the small number of independent genomes and paucity of HLA haplotypes, there was a greater likelihood that many Hutterite couples would share HLA antigens. In addition, Hutterite couples sharing HLA also shared alleles at nearby loci, allowing the effects of sharing alleles at undefined MHC loci to be evaluated [67].

The results of an earlier survey by Ober *et al*. in the Hutterite community showed that the intervals from marriage to each birth were no longer among couples sharing HLA compared with couples not sharing HLA, although differences did become significant at the second birth and remained so through the sixth birth (p < 0.05) [70]. When effects of individual loci on interval lengths were examined, HLA-DR was the only one whose effects on interval lengths were statistically significant, while sharing at other loci (HLA-A or HLA-B) had a smaller effect. It may be that the longer intervals to pregnancy among Hutterite couples sharing HLA-DR may result from recurrent peri-implantational losses [67].

Fetal loss rates were not different among couples sharing and not sharing HLA-DR, but were increased among couples sharing HLA-B as compared with couples not sharing HLA-B, suggesting that HLA-B or a closely linked locus influences fetal loss rates [52].

## **FETAL WASTAGE**

Reports regarding the association of consanguinity and fetal wastage are conflicting, according to studies from Sudan, Saudi Arabia and Jordan. In Saudi Arabia and Jordan the total prenatal losses were essentially the same for consanguineous and non-consanguineous couples [22, 28, 71]. Other studies reported similar results [21, 24, 35, 36, 72-74]; however, a higher rate of prenatal losses among consanguineous couples was observed in the Palestinian Territories [75]. The possible effects of consanguinity on abortion rate, stillbirths and neonatal deaths are shown in Tables **3, 4** and **5**.

**Table 3:** Rates of abortion associated with consanguinity according to previous studies

*Table 3: contd….*

\*CM = consanguineous marriage.

### *Consanguinity, Fertility, Reproduction Genetic Research to the Rescue!* **107**

*Table 4: contd….*

\*CM = consanguineous marriage.

A consanguinity study group of international experts and counselors met at the Geneva International Consanguinity Workshop in 2010 [11], and their deliberations on the known and presumptive risks and benefits of consanguineous marriages indicated that:

Bittles and Black investigated the impact of consanguinity on death from ~6 months gestation to an average of 10 years of age [87]. Using a meta analysis they compared the prereproductive mortality in first-cousin *versus* non-consanguineous progeny within specific populations. The study sample consisted of 69 populations resident in 15 countries located in four continents, giving a total sample size of 2.14 million. The results revealed a mean excess mortality at first cousin level of 3.5% (p < 0.00001). This estimate of 3.5% excess deaths among first cousin progeny was comparable with a previous estimate of 4.4% excess mortality calculated from 38 studies, each of which was included in the 1994 analysis [88] (Table **6**).

### *Consanguinity, Fertility, Reproduction Genetic Research to the Rescue!* **109**

**Location Infant Death Rates (%) References First Cousins More Distantly Related Unrelated**  The Netherlands – Native and Migrants. Between a quarter and a third of marriages are between first cousins. Hereditary causes of death in the Moroccan and Turkish populations are 4-5 times higher than in the Surinamese/Antillians and indigenous Dutch [89] Mauritanian ethnic groups The death rate among infants and young children in the Soninkes and Poulard groups is higher among consanguineous than non-consanguineous couples [45] Abu Dhabi Consanguinity is significantly associated with mortality in infants and children aged under 5 years but not with neonatal mortality [90] Israel The incidence of congenital malformations and Mendelian diseases correspond to the differences in the consanguinity rates between the Jewish and Arab populations [91] Egypt, Alexandria Consanguinity increased the relative risk of post-neonatal death and total reproductive losses [74] Jordan Consanguineous marriages showed significantly higher rates of stillbirths and infant mortality in general. Within the consanguineous group, female infant mortality rates were significantly higher than those of males [28] Norway The risk of recurrence of stillbirth and infant death is higher for offspring of first cousin parents compared with offspring of unrelated parents [84] Israel (Arab) 6.3 0 1.3 [73] Sudan No significant difference was observed between consanguineous and nonconsanguineous [22] South India – Post neonatal deaths 6.2 (includes uncle/niece unions) 5.7 5.3 [81] South India – Infant deaths 11.3 (includes uncle/niece unions) 9.2 9.3 [81] Japan No significant difference was observed between consanguineous and nonconsanguineous [82] Chicago, USA 6.3 0.6 [83]

**Table 6:** The rates of infant deaths associated with consanguinity found in previous studies

### **CONSANGUINITY, BIRTH OUTCOMES AND MEASUREMENTS**

Few studies have been conducted into possible associations between consanguinity and neonatal distress as measured by Apgar scores, and the results of investigations into the relationship between consanguinity and birth measurements have been mixed [18]. Some authors have reported that babies born to consanguineous parents are smaller and lighter than those born to nonconsanguineous couples, and therefore less likely to achieve developmental milestones or survive, while an approximately equal number found no significant consanguinity-associated difference. These contradictory findings may be a result of variability of the investigative protocols used, the use of simple "consanguineous" *versus* "non-consanguineous" comparisons, and limited or no control for possible confounding factors, such as socioeconomic status, maternal age, nutrition, health status and disease. The importance of these latter factors was shown in a study in Jordan [92]. While univariate analysis suggested a highly significant positive association between consanguinity and low birth weight, when the authors used multivariate analysis to control for age, body mass index, occupation, education, smoking, gravidity, parity, medical problems during pregnancy, and a family history of premature deliveries, the statistical significance of the association with consanguinity disappeared [92].

## **INFANT MORTALITY**

In 2004 Tarabeia *et al*. investigated the difference in infant mortality rates (IMR) between the Arab and Jewish populations in Israel, and found that, similar to the Jewish population, the IMR in the Arab community has decreased over the years, although it is still much higher than that in the Jewish community [93] (Fig. **1**). The continuing difference is attributed to the constantly high frequency of consanguineous marriages in the Arab Israeli population [8], together with a high rate of major congenital anomalies, many of which affect the central nervous system [94].

## **CONGENITAL ANOMALIES AND CONSANGUINITY**

Approximately 3-5% of all live newborns have a medically significant congenital anomaly. A report published in 2006 by the March of Dimes estimated birth defects to be >69.9/1000 live births in most Arab countries, as opposed to <52.1/1000 live births in Europe, North America and Australia [95]. These anomalies are mostly attributable to autosomal recessive diseases [3, 96, 97].

The association between consanguinity, genetic disorders and congenital malformations is discussed in Chapter 3, while the relationship between consanguinity and adult diseases is addressed in Chapter 4.

**Figure 1:** Trends in IMR by religion, 1970 – 2000 (rate per 1,000 live births). (Copyright (2004) Israel Medical Association Journal (IMAJ). Used with permission from Tarabeia J, Amitai Y, Green M, *et al.* Differences in infant mortality rates between Jews and Arabs in Israel, 1975-2000. Isr Med Assoc J 2004; 6: 403-7 [93]).

### **ACKNOWLEDGEMENTS**

The authors thank Dr. David Vardimon, M.D. for his invaluable assistance with the section on human leukocyte antigen (HLA) genes and pregnancy.

### **CONFLICT OF INTEREST**

The authors confirm that this chapter contents have no conflict of interest.

### **REFERENCES**

© 2014 The Author(s). Published by Bentham Science Publisher. This is an open access chapter published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode

# **CHAPTER 6**

# **Awareness and Knowledge about Consanguinity-Related Problems among Members of Communities Where the Custom is Prevalent**

## **Gabrielle J. Halpern1,\* and Lutfi Jaber2,3,4**

*1 The Raphael Recanati Genetic Institute, Rabin Medical Center, Beilinson Hospital, Petah Tikva, 49100, Israel; 2 The Bridge to Peace Community Pediatric Center, Taibe, 40400, Israel; 3 Institute of Neurology, Schneider Children's Medical Center of Israel, 14 Kaplan St., Petah Tikva, 49202, Israel; 4 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel*

**Abstract:** 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.

**Keywords:** Awareness, consanguineous marriages, counseling, education, high frequency, low genetic literacy, recessive genes, target groups.

**Lutfi A. Jaber and Gabrielle J. Halpern (Eds.) © 2014 The Author(s). Published by Bentham Science Publishers**

**\*Address correspondence to Gabrielle J. Halpern:** The Raphael Recanati Genetic Institute, Rabin Medical Center, Beilinson Hospital, Petah Tikva, 49100, Israel; Tel: +972-3-937-7659; Fax: +972-3-937-7660; E-mails<EMAIL_ADDRESS><EMAIL_ADDRESS>
### **118** *Genetic Research to the Rescue!*

### **INTRODUCTION**

Consanguineous marriages constitute over 50% of all marriages in many countries of the Middle East and Asia, and over 20% in several other countries (see Chapter 2). Throughout the world, more than 1,000 million people live in countries where between 20% and 50+% of marriages are consanguineous [1]. 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 a low level of genetic literacy among the public and most health care providers [2, 3], and this constitutes an enormous stumbling block when attempts are made to reduce the burden of consanguineous marriages, since if the members of the community have no knowledge about the problems associated with such marriages, or indeed are not even aware that problems exist at all, they will not be willing to change the marital pattern of hundreds of years and will strongly resent any attempts to do so. 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 (see Chapter 7).

## **ESTABLISHMENT OF EDUCATIONAL AND COUNSELING PROGRAMS – IDENTIFICATION OF TARGET GROUPS**

The main factor in establishing educational and counseling programs aimed at reducing the frequency of consanguineous marriages among the members of those communities in which it is high is to identify the target group(s) who would benefit most from such programs, with success being measured by a reduction in the rate of these marriages among the participants of the programs. In order to identify the target group(s) in a specific community, preliminary studies have to be carried out to assess the levels of awareness about problems associated with consanguineous marriages among the people in the community.

An example of this is the survey carried out by Jaber *et al*. in 1999 in which the level of knowledge about the issues associated with consanguinity was evaluated

among adolescents (tenth grade students) in the Israeli Arab community in order to try to obtain information about which groups should be targeted for educational programs [4]. This age group was selected because these youngsters would be thinking about choosing a partner in the near future. The schools that participated in this survey were chosen randomly, and since attendance at high schools is compulsory in Israel, the group of students included in the survey was representative of this age group. A total of 2933 Israeli Arab students aged 15-16 years were interviewed by means of a written questionnaire, which included questions on demographic characteristics, questions that assessed the level of knowledge of the respondents regarding the issue of consanguinity, and questions that addressed the students' attitudes and behavior toward the question of consanguinity. The list of conditions given in the questionnaire that it is possible for a baby to be born with or that children of consanguineous parents are more likely to suffer from compared with children of unrelated parents intentionally included "throat infection". This, of course, is not congenital, and the reason for including it was to distinguish between those students who did not know what congenital disorders were, and answered "yes" to this question, and those who did know that throat infection was not a congenital disorder.

The percentage of girls with a high level of knowledge was significantly higher than the percentage of boys (27.9% compared with 22.3%), but no significant differences were found between the responses of the Muslim students as compared with those of the Christian students. Students living in urban areas had a lower level of knowledge than those from the rural and suburban areas. There was no association between the age of the students' parents at marriage and the level of knowledge of the students. The level of education of the parents was significantly associated with the level of knowledge of the students; children of parents with lower levels of education had a lower level of knowledge. The level of knowledge was also lower among students whose parents were consanguineous compared with those whose parents were unrelated. A comparison of the level of knowledge between students with siblings married to relatives *vs*. those whose siblings were not married to relatives found no significant difference.

The students were asked whether any of their brothers or sisters suffered from congenital disorders such as deafness, mental retardation, or blindness. Those students who had siblings with congenital disorders demonstrated a significantly lower level of knowledge about consanguinity.

The students were asked the following question in order to assess their awareness of an association between consanguinity and specific congenital disorders: "Is it more likely that children of consanguineous parents will suffer from congenital disorders such as deafness, mental retardation, blindness, heart defect, anomalies of extremities, or throat infection, compared with children of unrelated parents?" According to their answers it was possible to assess the percentage of students who knew what was meant by the term "congenital disorders", and who understood the association between such disorders and consanguinity. The percentages of students giving correct answers to this question were: deafness, 43.8%, mental retardation, 58.6%, blindness, 31.0%, heart defect, 45.5%, anomalies of extremities, 53.3%, and throat infection, 48.2%. Among the students who knew what congenital disorders were, a higher percentage knew that there was an association between these and consanguinity compared with students who did not know what congenital disorders were.

The overall results of this survey revealed that almost half (45.8%) of the respondents to the questionnaire had a low level of knowledge about consanguinity, and only 24.5% had a high level of knowledge [4]. The rest (29.7%) had a moderate level of knowledge. There was a generally low level of knowledge among male students, among the offspring of parents with low levels of education, among the offspring of consanguineous parents, and among students with extreme religious attitudes. These factors should be taken into account when planning the educational programs in the schools.

# **ACCEPTANCE OF PRENATAL DIAGNOSIS AND TERMINATION OF PREGNANCY**

Another important consideration is the acceptance by the community of prenatal diagnosis and termination of pregnancy in the case of an affected fetus. In a survey in the Israeli Arab community, 231 women of childbearing age were interviewed three days postpartum to assess their knowledge of prenatal diagnosis and termination of pregnancy, their willingness to undergo prenatal diagnosis, and

their attitudes towards termination of pregnancy in the event that the fetus was affected with a severe congenital malformation or genetic disease [5]. Half the women believed that prenatal testing was not an accurate or effective method for diagnosing an affected fetus. A quarter had poor knowledge about prenatal diagnosis, and a quarter believed that prenatal diagnosis does provide the correct diagnosis. Ninety-five percent said they would agree to undergo prenatal diagnosis, and in the event of a severely affected fetus, 36% said they would agree to a termination of pregnancy, 57% said they would not, and 7% were undecided. The authors pointed out that there is a need for special intervention programs, with guidance by health professionals, geneticists and religious authorities, to educate this population about the increased risk associated with consanguinity, to stress the importance and effectiveness of prenatal testing, and to encourage them to accept prenatal diagnosis and termination of pregnancy if indicated [5].

Zahed *et al*. conducted two studies in Lebanon, the first [6] involving 83 couples at risk for a hemoglobin disorder, mainly beta-thalassemia, and the second [7] comprising 90 couples at risk for various genetic disorders, in order to assess their acceptance of prenatal diagnosis and the factors that may influence their decision. In each survey, of those who refused, a large majority said that the reason for their refusal was because of religious conviction against termination of pregnancy. Only 12 percent of the couples understood and were aware of their genetic risk, and the authors commented that for prevention of genetic disorders, the emphasis in countries such as Lebanon should be placed on public awareness about genetic risks, the risks of consanguinity and availability of services, while taking into account the personal beliefs of the individuals [7].

In a survey in Saudi Arabia, Babay investigated the attitude of 550 pregnant women aged >35 years to prenatal screening for chromosomal anomalies [8]. Even though chromosomal anomalies are not connected with consanguinity, the results of this survey shed light on the general attitudes of Saudi women regarding prenatal screening and termination of pregnancy. A total of 336 women (61.1%) accepted the general idea of prenatal screening, 160 (29.1%) did not, and 54 women (9.8%) were undecided. Non-invasive methods such as ultrasound and biochemical screening were well accepted (61.35% and 53.0% respectively), but invasive methods less so (34.2%). Seventy-six percent would not agree to termination of pregnancy in the event of an abnormal result, 22% did not accept screening in general as they doubted that the tests were accurate, 19% did not believe that they would have an abnormal child, and 6% did not believe that screening should be carried out for chromosomal anomalies. The main reason why they refused screening was the unacceptability of termination of pregnancy as a treatment option [8].

Tsianakas and Liamputtong examined how immigrant Muslim women living in Australia perceived and experienced prenatal testing [9]. They also looked at the opinions of the women's partners. The authors conducted in-depth interviews with the women and found that they had, in general, positive attitudes toward prenatal testing, particularly ultrasound, although some were ambivalent about amniocentesis. In spite of their doubts, the women tended to agree to prenatal testing as they believed it was a routine part of antenatal care and "confirmed their own perceptions of being a 'normal mother', who should accept advice from their doctors". The partners of the women in the study also played an important role in the acceptance of prenatal testing. The authors suggested that women should be given a choice rather than being pressured and "made to conform to the routinization of prenatal testing", and this would enable sensitive health care to be provided for women in general and for Muslim immigrant women in particular [9].

Durosinmi *et al*. examined the acceptability of prenatal diagnosis for sickle cell anemia (SCA) as a means of controlling sickle cell disorder in Nigeria by means of a structured questionnaire [10]. The respondents were 92 adult female patients with SCA, 53 carrier mothers (*i.e.* who had sickle-cell trait), and 48 carrier fathers. More than 85% of the respondents said they would like prenatal diagnosis to be offered in Nigeria; 92% of the mothers and 86% of the fathers said they would like to undergo, or would like their wives to undergo, this procedure. However, only 35% of the patients as opposed to 63% of the mothers and 51% of the fathers would opt for termination of an affected pregnancy. The main reasons given for refusing termination were religious convictions and the fear of the complications of abortion. The high percentage of parents who would opt for termination of pregnancy was connected with the general desire in the community for "perfection" and on their previous experience of managing a patient with SCA. Most of the respondents considered effective genetic counseling as the best means of controlling SCA. When the respondents were asked their views about the transmission of SCA, 68% of the patients and 79% of the fathers knew it was from both parents, but only 47% of the mothers knew this. In fact, 30% of the mothers attributed SCA to an "act of God", while only 8% of the fathers and none of the patients gave this as the cause.

## **ATTITUDES TO CONSANGUINITY**

In a survey by Jaber *et al*. in the Israeli Arab community, respondents (mostly fathers, occasionally mothers if fathers were unavailable, of second-graders) were asked to rate their opinion of consanguineous marriage according to a 5-point scale. Those whose own marriages were consanguineous were considerably more likely to strongly encourage such a union, and therefore this group should also be a main target group for counseling and education [11]. A similar result was obtained by Khlat *et al*. among a sample of women in a hospital setting in Beirut [12], and in a review of the spectrum of genetic diseases in Bahrain, al-Arrayed found that 53% of respondents were in favor of consanguineous marriage, 62% agreed it could cause genetic disease, and 47.8% agreed it could cause social problems [13].

A survey in Saudi Arabia among 32 families with children affected with hemoglobinopathies found that 17 (53.1%) participants had a negative attitude towards consanguinity [14]. Among these, five (15.6%) participants continued to have a negative attitude towards consanguinity and 12 (37.5%) changed their attitude from positive or ambivalent to negative or less positive after their experience with their own affected children, *i.e.* they would no longer encourage consanguineous marriages. Eleven (34.4%) participants had a positive attitude towards consanguinity, four (12.5%) would encourage consanguineous marriage provided premarital screening would be carried out, while four (12.5%) remained ambivalent.

## **SURVEYS AMONG SPECIFIC ETHNIC GROUPS**

A paper by Shaw and Hurst describes in detail the results of an investigation into the understanding of genetics, illness causality and inheritance among British

### **124** *Genetic Research to the Rescue!*

Pakistanis referred to a genetics clinic in England [15]. The participants were interviewed either in English or Urdu, and the sessions revealed that a wide selection of environmental, behavioral and spiritual factors were perceived as being the causes of medical and intellectual problems. Misconceptions about where in the body genetic information is located and of genetic mechanisms of inheritance were common and included the belief that a child receives more genetic material from the father than from the mother. Despite the "conversational" use of genetic terminology by some participants, it was apparent that some patients had absorbed genetic information in ways that were at variance with genetic knowledge with potentially serious clinical consequences. Moreover, the patients were skeptical of genetic theories of illness, thus reflecting their rejection of the prevailing opinion that cousin marriages do carry a genetic risk. The authors remarked that patients referred to genetics clinics may not easily dispense with their personal theories about the causes of their own or their child's condition and their understandings about genetic risk. This paper provides a wealth of evidence that genetic counselors, and indeed other health professionals as well, who work in Western countries and for whom consanguinity might previously have been merely something they may have read about but not personally encountered, need to become experts when working with immigrant communities such as Pakistanis in order to be able to identify, work with, and possibly challenge patients' understandings of illness causality and inheritance [15].

In another study carried out among the Pakistani community in England, Ahmed *et al*. interviewed after they had received their results 43 pregnant women who were tested for thalassemia carrier status [16]. One purpose of the survey was to determine the women's awareness of and attitudes towards prenatal diagnosis and how this affected their attitudes towards the termination of an affected fetus. The survey also examined whether the women's religious beliefs influenced their attitudes towards termination of pregnancy, how they perceived the severity of the condition, the influence of other people important to them, and gestational age at the time that termination was offered. Analysis of the results revealed that most women who decided to undergo prenatal diagnosis did so not because they wanted to terminate an affected fetus, but because they wanted to know whether their baby had thalassemia, in order to be able to prepare themselves emotionally and physically and make financial arrangements for caring for the child. They would also be able learn about the condition that the child has and the treatment(s) available.

The authors also commented that sometimes women at-risk refused prenatal diagnosis or agreed to terminate an affected fetus because they did not feel that they could agree to prenatal diagnosis without concomitantly agreeing to undergo termination in the event of an affected fetus. To enable couples to make informed decisions, it should be made clear to them that the offer of prenatal diagnosis is not dependent on their agreement to terminate an affected pregnancy [16].

The findings of this study also showed that religion was an important factor in the decision-making about termination of pregnancy. Information about Islam's position on termination for a serious disorder enables parents to consider this more favorably. There is a difference of opinion between Islamic scholars as to whether "ensoulment" occurs at 40 or 120 days, depending on different interpretations of a specific Hadith. However, all the scholars agree that embryonic life is entitled to respect even before "ensoulment", and even more so afterwards [17]. Muslim religious teaching allows termination of pregnancy within the first 120 days after conception in the event of a severely affected embryo, but abortion after 120 days is considered a criminal offense and is prohibited by all Islamic scholars. Because of this, in the study by Ahmed *et al*. [16], the timing of the offer of termination of pregnancy was important; the women were more likely to agree if it were offered in the first trimester and the authors therefore recommended that prenatal diagnosis should be made available to all at-risk couples in the first trimester.

Many of the women considered that their risk of having a child with β-thalassemia major was "fate". Such beliefs may have been influenced to some extent by their Islamic faith, but also by their social class, educational background and age. The findings also showed that religion was not always the major factor in the women's decisions about prenatal diagnosis and/or termination of pregnancy, but that their perceptions of the severity of β-thalassemia major were also likely to be an important consideration. In other words, the more severe their perceptions of β-thalassemia major, the more likely they were to agree to termination of an affected fetus [16].

Another factor revealed by this study was that family members were also involved in the decision-making process and tended to encourage prenatal diagnosis and termination of pregnancy, especially if they were aware of the problems associated with β-thalassemia major. The positive aspect of involving other family members in the decision making process is that the couple would not have to worry about the consequences of their decision alone. If the decision is made collectively with a supportive family, the couple will feel more comfortable with the decision to terminate an affected fetus, or to continue the pregnancy knowing that the family will be involved in helping to care for a child with β-thalassemia major [16].

Another study describing lay perceptions of genetic risks attributable to consanguinity among Pakistanis was carried out by Hussain over a 7 month period in 1995 [18]. This study, however, was conducted in Pakistan, in four lowincome, multi-religious, and multi-ethnic squatter settlements in Karachi. The study was carried out in two stages, the first of which consisted of a demographic survey of a random sample of 1,011 ever-married women aged between 15 and 49 years. The second comprised focus-group discussions and in-depth, semistructured, face-to-face interviews. The participants were 294 women who had ever been married and who were 30 years of age or older at the time of the study. The questions focused on the women's perceptions and experiences of close consanguineous marriages, including social and health advantages and disadvantages of such marriages. Only those respondents who knew that consanguineous marriages could increase the risk of health problems were asked to list the type of conditions associated with consanguinity.

The main religions of the participants were Muslim (71%), Christian (24.5%) and Hindu (4.5%). Among the Muslims, 65.1% were in consanguineous marriages, among the Christians the figure was 38.9%, and among Hindus 23.1% were married to a relative. Over 80% of the consanguineous couples were married to first cousins, and approximately 55% of respondents reported that their parents had also been close cousins [18]. When the group discussion participants were

asked to describe the advantages and disadvantages of consanguineous marriages for the health of their offspring, most of them said that such unions did not lead to adverse health effects in the offspring. Many agreed with the commonly held belief that "illness comes from God" or was a result of "nazar" ("evil eye"). However, some of the participants did acknowledge that if one or both parents were affected by a particular illness there was an increased likelihood of their children being affected by the same disease. By comparison, approximately onehalf of the respondents (51%) from the in-depth interviews understood that consanguineous marriages increased the risk of inherited disorders. Responses included statements such as "illness came from God" (4%) and "no knowledge on the issue" (7%). The fact that most children, except those with gross malformations, appeared normal at birth and later became ill was frequently cited in group discussions as evidence for the influence of the "evil eye". Some of the participants said that although they themselves were not convinced that consanguineous marriages had an adverse effect on the health of the offspring, medical doctors often emphasized the fact that several illnesses could be attributed to the practice of cousin marriage. Nevertheless, very few women said that they would reconsider their decision of a consanguineous marriage for their children on the basis of health problems in the parental generation [18].

Their perceptions of risk varied according to the educational status of the respondents. Among women with no formal education, there was little difference in the proportion of participants reporting an association between inbreeding and risk of ill-health in the offspring between women who were in consanguineous marriages and those who were not. However, among participants with primary or secondary education, more consanguineously married participants said that the risk of genetic disorders was higher among children of consanguineously married parents. There was no appreciable difference in perceptions about adverse effects of consanguineous marriage by religious affiliation of the respondents [18].

The absence of observable defects in all the children of consanguineous marriages appeared to create much confusion with regard to the genetic origins of disease. A common question was "if the problem (medical condition) is genetic in origin, then why are not all the children of a consanguineously married couple affected?" The lack of a uniform outcome across families was very frequently given as an example of how "doctors have got it all wrong". Furthermore, the respondents appeared confused that some of the diseases that the doctors said were due to the practice of marrying within the family did not appear until later in life, "which made little sense as the illness must have been in the 'blood' all along and should have manifested much earlier" [18].

Respondents who knew that consanguinity increased the risk of inherited disorders were asked which types of illness might affect the offspring of consanguineous marriages. Most of the responses fell into three broad categories: infections – for example tuberculosis, chronic diseases such as diabetes, hypertension and asthma, and malignancies. Many participants thought that disability in the offspring resulted from problems with compatibility of the husband and wife's blood groups, and therefore perceptions of genetic risk were considered to be insignificant as long as the couple had compatible blood groups [18].

This study underscores the need for additional research in order to quantify the health risks associated with consanguineous marriages in Pakistan and to determine community perceptions of these risks among different population subgroups. The author described as equally important the need for the Pakistani medical community also to understand these issues, both from a medical point of view and according to the prevailing socio-cultural norms. Furthermore, given the general level of confusion among general practitioners regarding medical conditions associated with consanguinity, the author suggested that there is an urgent need to include the basics of genetic counseling in the medical curriculum and to provide appropriate information through continuing education workshops. The author also pointed out that it is important to determine the attitudes of the community towards premarital and prenatal screening, especially among high-risk families, and to assess the acceptability of pregnancy termination services. Because of the complexity of these issues, in addition to the medical personnel, the active engagement of religious and community leaders would be required to formulate policies that are both religiously appropriate and culturally sensitive. While it is acknowledged that consanguineous marriages offer many social advantages in the Pakistani setting, as in all the communities in which this type of marriage is prevalent, it is essential to balance these benefits against the health

costs, both social and economic, so that the communities can make informed choices about consanguineous marriages [18].

Like the Pakistani interviewees in the paper by Hussain [18], a group of Saudi Arabian parents also had difficulty accepting a genetic explanation for diseases that did not affect all the children at the time of birth and they also expressed religious or folk beliefs to account for illness [19]. Thirty-six Saudi families with children who suffered from neuro-metabolic disorders were interviewed at a specialist hospital in Riyadh in order to assess parental understanding of disease and attitudes towards future births and consanguineous marriages. At the time the survey was performed (1988), the frequency of consanguineous marriages in Saudi Arabia was 54.3% overall, 31.4% for first cousins, and in general the rates were higher among the Bedouin [20]. A more recent assessment of the frequency of consanguineous marriages puts those between first cousins at 33.6% and those between more distant relatives at 22.4%, giving an overall rate of 56% [21], indicating that in the intervening years no significant changes in the frequency have taken place.

The survey by Panter-Brick [19] focused only on families with children with metabolic disorders and thus was not representative of the general spectrum of diseases in the Saudi-Arabian population; however, the attitudes and opinions of the families can be regarded as representative since these were not specific to specific illnesses. The parents were interviewed by semi-structured questionnaires. Knowledge about the disease was ascertained from the family's belief in its underlying cause, recognition of symptoms, expectation of progress or fatal outcome, and awareness of specific treatment, and then the social, financial and emotional burden of caring for the sick child was discussed. The parents' attitudes towards marriage and family planning were explored by asking them whether they wished to have more children, preferred consanguineous marriages to non-consanguineous ones, and would want their children to marry a close relative. Parental explanations for disease included statements such as: "God's will", "genetics", "I don't know", the "evil eye", and "illness during childbearing". All the parents believed that "God determined their fate in granting health or illness". Some acknowledged that the disease had a genetic basis without really accepting or understanding it. Many said they had no idea what could be a possible cause, mainly because they did not believe the medical explanations they had been given or because they did not want to reveal beliefs of a non-medical nature [19].

Parents only acknowledged that a disease was inherited if this was clearly the case according to the family history. They thought that if a disease was genetic then all the children should be affected and not just some, and that the illness should manifest immediately after birth rather than some time later. They stressed the fact that they had relatives who had married cousins but who had normal children, and conversely that brothers who had married outside the family had affected children. However, they did acknowledge that they were carriers where the disease was clearly apparent in the husband's or the wife's pedigree. The risks to future pregnancies were poorly understood; of eight parents who stated what they thought was a probability for future children being affected, only four did so correctly [19]. Two-thirds of the respondents acknowledged that the disease might have a genetic basis, but only a third of them were certain.

Parents centered their explanations for the occurrence of the disease around religious belief, whether or not they had acknowledged heredity, because to them this provided a better reason. One mother expressed this as follows: "the disease runs in my family. But only God knows why some children are fine and others are not". Some parents said that they believed "their burden was willed by God and should be borne patiently". This helped the parents to overcome their feelings of anger or helplessness and they would say "I must accept His will". The more religiously devout families regarded their suffering as a test of their faith. Religion also allowed them to deny responsibility; unlike in the West, only a few of the parents felt a sense of guilt for having given birth to a child who had to suffer. While most mothers worried that future offspring might be affected, others did not, since "God would provide". Religious beliefs also enabled the parents to hope that the child would survive, since Islam accepts that surrendering to God's will does not prevent people from seeking a cure. Religion offers them a more acceptable explanation for the disease; parents prefer to relate the reason for individual suffering to "God's will rather than chance events: there is a purpose to God's action that cannot be attributed to 'blind' probability" [19].

Many of the parents said that belief in the "evil eye" was also a factor in explaining why some children who were perfectly healthy at birth and growing normally were suddenly afflicted with a serious illness. The "eye" – also known as the "look" – "is cast by females, who may be jealous, envious or simply wicked, and who intentionally or unintentionally harm a child at a glance". Some parents cited infectious illnesses (*e.g.* meningitis) and taking the contraceptive pill during pregnancy or early lactation as causes for a child's failure to thrive. Consistent with the variety of explanations, families sought a combination of cures among Quranic readers, local healers and empirical medicine [19].

The attitudes of the respondents towards marriage between close relatives were approximately equally divided between those who were in favor and those who were against. Thirteen parents thought that cousin marriages were preferable to those between non-relatives because the families knew one another and this strengthened the relationships between them. Fourteen parents stated that they would discourage their children from marrying a close relative, while another three said that they would merely advise them against doing so. One father suggested banning all consanguineous marriages for the next several generations, while two mothers said "the modern way" was to undergo testing before marriage to determine whether a prospective couple carried any diseases [19].

Slightly more than half of the parents said they had a good understanding of heredity and as a result of this awareness they had a cautious attitude towards future births and marriages. There was a significant association between the consistency of their responses and the education of both husbands and wives. However, contrary to expectation, the type of response was not significantly associated with their past experience of the disease. The author commented that Saudi parents may well have difficulty in comprehending the complex rules of genetic inheritance, especially if they have had little schooling. She also pointed out that women in particular felt unable to question male physicians. In addition, parents may be unwilling to accept a genetic explanation for something that is a very sensitive family matter [19].

A survey of childhood blindness in Saudi Arabia, which showed significant association with consanguinity, recommended "a comprehensive program of religious and governmental intervention to discourage marriage between persons having the same grandfather or grandmother" [22]. However, it is difficult to implement such a program in Saudi Arabia as this involves a very sensitive issue which most people consider lies solely in the family domain. At the present time, general education in genetics is available only to those who attend high school. However, local newspapers and some television programs have begun to draw public attention to the subject [19].

The establishment of a screening program for identifying families at particular risk of genetic disease is a realistic objective in Saudi Arabia [19]. In meetings, parents showed great interest in the rules of genetic inheritance and the possibilities for screening relatives before marriage. Awareness of medical facts may not offer much emotional comfort to parents, but it does allow for future preventive measures through pre-marital screening to identify adult carriers and the early diagnosis of affected infants.

Khlat *et al*. conducted a survey in 1984 and 1985 in Beirut among 100 women who had married relatives and a matched group of 100 women who had married non-relatives [9]. One purpose of the questionnaire was to assess the women's perception of consanguineous marriages, and a second was to evaluate their awareness of the genetic risks to which these expose the offspring. Among the women in consanguineous marriages, 72% thought that marrying a relative was advantageous, while only 12% of the matched women agreed (the remainder may not have wanted to appear to underrate their own marriage as one of lower quality). Furthermore, 48% of the women who had married a relative, as compared with 12% of the matched women, indicated a preference for cousin marriage rather than marriage between non-relatives. The women in consanguineous marriages cited "ill-effects on offspring's health" as the main argument against cousin marriage, while the matched women said that the main one was "does not extend family". For them, "ill-effects on offspring's health" was the second argument. Nearly twice as many of the matched women (66%) compared with the women who had married a relative (36%) were aware of the increased risk of inherited disease among offspring of consanguineous marriages. However, both groups recognized to a similar extent the importance of counseling by a physician before a marriage between relatives. Even though only 12% of the

matched women expressed a favorable attitude towards marriages between relatives, almost half of them (49%) would still advise their son/daughter to marry his/her cousin, while 53% of the women who had married a relative would do likewise [9].

Kisioglu *et al*. carried out a study in 2007 to examine the effects of a formal training program on consanguineous marriages on the knowledge of, and attitudes towards, consanguineous marriage of high school students in the Mediterranean region of Turkey [23]. Prior to and after completion of the training program, questionnaires were administered to the participants in order to assess the effectiveness of the program. The program was aimed at educating the students about consanguineous marriages.

The questionnaire consisted of 37 questions, of which 7 were descriptive questions (name, gender, school name, *etc.*), 15 were about sociodemographical features of the students and their families (birth place, educational status, job, monthly income, number of siblings, consanguinity), and 15 were designed to assess the students' knowledge of consanguineous marriage and their attitudes towards the issue. Prior to the program, the general level of awareness of the role of heredity in the causation of thalassemia was low – only 39% of the students thought that this was the cause – whereas after the program this figure increased to 96.3%. Other questions about thalassemia revealed a similar lack of knowledge before the program, with a significant improvement after. Asked whether they would consider consanguineous marriage for the future, before education 83.5% said no, while after education 93.9% said they would not consider this [23].

In a survey conducted in Qatar, a higher proportion of respondents reported that they were aware that the risk of congenital anomalies and genetic problems were increased with consanguinity [24]. Seventy percent of the offspring of non-related parents knew of the risk of blood diseases such as thalassemia and sickle cell anemia, whereas only 54% of consanguineous and 60% of tribal offspring knew this. Fifty-two percent of offspring of non-related parents knew of the increased risk for inborn errors of metabolism in consanguineous offspring, and similar results were found regarding the risk of deafness, anomalies of extremities and heart conditions, all of which can be associated with autosomal recessive transmission and consanguinity. More than 50% of the participants thought that the occurrence of Down syndrome could be increased with consanguinity, although the evidence to support such an association has been conflicting.

Overall, there is still much work to be done to increase knowledge and awareness of the problems associated with consanguinity among the majority of the members of the communities in which consanguineous marriages are still the preferred type of union. Education, discussed in chapter 7, and genetic intervention, discussed in chapter 8, offer the best prospects for future management.

### **ACKNOWLEDGEMENTS**

Declared none.

## **CONFLICT OF INTEREST**

The authors confirm that this chapter contents have no conflict of interest.

## **REFERENCES**

http://www.gfmer.ch/Medical\_genetics\_education\_research/Strategies\_care\_prevention\_bir th\_defects\_Jordan\_model\_Hamamy\_2009.htm

© 2014 The Author(s). Published by Bentham Science Publisher. This is an open access chapter published under CC BY 4.0 https://creativecommons.org/licenses/by/4.0/legalcode

# **CHAPTER 7**

## **Future Strategies 1 – Educational and Counseling Programs**

**Gabrielle J. Halpern1,\* and Lutfi Jaber2,3,4**

*1 The Raphael Recanati Genetic Institute, Rabin Medical Center, Beilinson Hospital, Petah Tikva, 49100, Israel; 2 The Bridge to Peace Community Pediatric Center, Taibe, Israel; 3 Institute of Neurology, Schneider Children's Medical Center of Israel, 14 Kaplan St., Petah Tikva, 49202, Israel; 4 Sackler Faculty of Medicine, Tel Aviv University, Tel Aviv, 69978, Israel*

**Abstract:** 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.

**Keywords:** Consanguineous marriages, counseling, education, frequency, recessive genes, religious intervention.

### **INTRODUCTION**

Even though most people accept that consanguinity can have a deleterious effect

**Lutfi A. Jaber and Gabrielle J. Halpern (Eds.) © 2014 The Author(s). Published by Bentham Science Publishers**

**\*Address correspondence to Gabrielle J. Halpern:** The Raphael Recanati Genetic Institute, Rabin Medical Center, Beilinson Hospital, Petah Tikva, 49100, Israel; Tel: +972-3-937-7659; Fax: +972-3-937-7660; E-mails<EMAIL_ADDRESS><EMAIL_ADDRESS>
### *Future Strategies – Education, Counseling Genetic Research to the Rescue!* **137**