In this study we show that in an extremely consanguineous population the incidence of IMD is significantly higher than that of a relatively non consanguineous population. This finding is expected since 80% of IMD are inherited in an autosomal recessive pattern. Yet, these data are important. IMD can be life threatening and the therapies for such disease can be extremely expensive28. Health policy makers should be aware that these devastating diseases are relatively common and not rare as expected, in extremely consanguineous populations. In the Bedouin populations IMD occur in at least 1/1000 live births. Prevention of IMD is possible after genetic diagnosis and genetic counselling to at risk families and this should be encouraged. Although consanguinity is considered to be rare in developed countries, in many populations in different geographic areas, consanguinity is common, suggesting that IMD as well as other genetic diseases are extremely more common in these populations.
Although the incidence of genetic diseases reflects the prevalence of genetic mutations in the population, it is noteworthy that the Bedouin population tends to have larger families. This can also affect the total incidence of IMD shown in this study. Since our aim was to compare the "real life" incidences of IMD in these populations, we did not use statistical methods to account for the possibility of a mother having more than one affected child. As a result, we did not calculate the prevalence of genetic mutations in the populations studied.
Additionally, there is a higher rate of absent prenatal care and lower rate of pregnancy termination, even with diagnosed devastating diseases, in the Bedouin population29,30. In order to prevent these cases, prenatal and premarital genetic consultation should be encouraged by all the caregivers of affected families, including raising the possibilities of Pre-implantation Genetic Diagnosis (PGD).
Since the Bedouin population has a high rate of consanguinity, there is also an increased number of founder effect, and the combination of large inbreeding families with high consanguinity rate is expected to result in a higher number of, although rare, recurring mutations in this population.
The only disease with a significantly higher prevalence in the Jewish population is glycogen storage disease type IIIA. All patients are homozygous to 4,455delT in the AGL gene as reported by Parvari et al31, that share a similar phenotype and originate from Northern Africa with a calculated prevalence 1:5,400 and a carrier prevalence 1:35 amongst North African Jews which is the result of a founder effect (Table 2). Additionally, glycogen storage disease type 1 A is more common, though not significantly, in the Jewish population of Ashkenazi origin with all patients being homozygous to the same mutation- R83C in the G6Pase gene32, resulting from a founder effect. The current estimated consanguinity rate amongst the Jewish population is 2.3% with an inbreeding coefficient of 0.0007033. . In Southern Israel, in the Negev area there are less Ashkenazi Jews than in other parts of Israel, and there is a high rate of marriage between Jews from different communities that leads to a decreased prevalence of autosomal recessive Ashkenazi diseases.
A limitation of our study is that patients’ recollection for this study had been performed in the pre and post introduction of the national newborn screening program in 2008. The Israeli Newborn Screening program includes nine IMD30. Since its inception, there might be an increasing diagnostic rate for the relevant diseases in our study (MCAD, VLCAD and MSUD),however, as can be seen in our study, most of the common diseases in Southern Israel are not screened in the extended screening therefore its detection rate is not expected to change between the pre and post newborn screening era. Zlotogora et al reported of a significant increase in the number of genes with variants causing autosomal recessive diseases among Israeli Arabs in the last several years34. It was presumed that it is mostly the result of the availability of better diagnostic possibilities for molecular diagnosis in genes already well known. Therefore, we should take into consideration that prior to this screening the diagnosed patients were those with relatively more severe clinical course. The above mentioned led us to the conclusion that prior to the universal newborn screening there was underestimation of the “true” incidence of IMDs. Also, we assume that even now there is still an underestimation of the “true” incidence, given the fact that many of these diseases are still not diagnosed (for example, in cases of early mortality or in cases of subtle disease that has not included in the newborn screening yet) and most of them are not included in the extended newborn screening program.
The high prevalence of certain diseases in different Bedouin clans as part of the total Bedouin population led to an additional genetic consultation to the different clans accordingly. Raz et al has revealed that although there is growing awareness of the association between cousin or other consanguineous marriage and genetic diseases including IMD, due to traditional aspects that involve solidarity, preservation of family property, social protection for women and parental authority there is even nowadays a high rate of intrafamilial marriages35. Another important factor that counterbalances the importance of underreporting that is common in the Bedouin community and should be taken into consideration is the difference in number of births between the Bedouin women and Jewish women in the Negev area, with a total fertility rate of 7.28 per Bedouin woman versus total fertility rate of 2.75 per Jewish woman36. Therefore, premarital carrier matching, which is already performed in ultra-orthodox communities can be a major factor in reducing the prevalence of IMD in this community.