Applied cultural and social studies are needed for a sustainable reduction of genetic disease incidence

Abstract

While clinical and basic biomedical research focus on diagnoses and cures for common and rare genetic diseases, they are unable to address one of the largest underlying causes for genetic disease: mating within families or other small genetically isolated sub-populations. This interdisciplinary literature study investigates theoretical, moral and practical aspects to solve this major cause for genetic disease from an alternative angle: through cultural change and encouragement of an outbreeding reproductive behavior. Understanding why some communities persist with choosing consanguineous reproductive partners when the modern society has eliminated the economic rationale to do so, and to develop strategies to encourage a cultural change in those communities, is critical for a sustainable long-term solution to reduce the number of new cases of genetic disease and undiagnosed (sub-clinical) but detrimental genetic abnormalities in vulnerable and marginalized groups in modern Western societies.

A CARD9 Founder Mutation Disrupts NF-κB Signaling by Inhibiting BCL10 and MALT1 Recruitment and Signalosome Formation

“…Targeted resequencing of the R70W mutation in 68 healthy Turkish individuals from the Istanbul region (results not shown) showed that the allele was absent there, suggesting that it may be geographically confined to the rural provinces of Afyonkarahisar and Eskişehir, where a tradition of consanguineous marriages promotes passing on of recessive disease ( 31 ). At this moment, we have no evidence that the R70W CARD9 mutation would provide any beneficial traits to the population, and its presence could thus be a direct consequence of endogamy within a small and genetically homogenous population, where a detrimental recessive allele became common through the founder effect ( 32 , 33 ). Earlier research has already shown a common founder origin for another CARD9 mutation [Q289 * ; ( 7 )] of middle-eastern origin, which raises the idea that CARD9 heterozygosity may offer a certain protective effect in populations from the greater Mediterranean basin.…”

Chimeric and mutant CARD9 constructs enable analyses of conserved and diverged autoinhibition mechanisms in the CARD-CC protein family

“…The dominant nature of the gain-of-function activating mutations allowed us to identify potential novel disease associations with the six activated CARD9 variants and three activated CARD10 variants that we identified in our screening. In contrast, rare recessive loss-of-function mutations are often only causing disease in populations with high levels of endogamy [75], which would have been difficult to pick up in Genebass due to limited ethnic diversity in the UK Biobank dataset [57]. Hopefully will there be similar initiatives globally that can increase both the number of datapoints for higher confidence in super-rare variants and for better inclusion and coverage of the human diversity.…”

Chimeric and mutant CARD9 constructs enable analyses of conserved and diverged autoinhibition mechanisms in the CARD‐CC protein family

“…The dominant nature of the gain‐of‐function activating mutations allowed us to identify potential novel disease associations with the six activated CARD9 variants and three activated CARD10 variants that we identified in our screening. In contrast, rare recessive loss‐of‐function mutations are often only causing disease in populations with high levels of endogamy [91], which would have been difficult to pick up in Genebass due to limited ethnic diversity in the UK Biobank dataset [63].…”