Considerations in consanguineous populations

In almost all regions in the world, there will be populations where consanguineous relationships are practised. In some regions, like the Middle East, Africa, and South Asia, consanguineous marriages are relatively common.

While offering cultural and social benefits, they also present unique challenges in healthcare, particularly in deciphering the complexities of genetic variations. With the explosion of exome and genome sequencing technologies, we’re witnessing a plethora of genetic variants being identified, each requiring meticulous interpretation to determine their impact on health. However, this process holds unique complexities in consanguineous families, demanding specialized approaches to navigate variant interpretation.

One major challenge lies in the frequent occurrence of multiple homozygous candidate variants within individuals. While the ACMG criteria provide valuable guidelines for classifying variants, assigning statistical power to segregation data in heavily inbred families proves daunting. This is due to the large number of homozygous variants of uncertain significance (VUS) present in their genomes. Some tools like ConsCal offer a glimmer of hope. By simplifying recurrence risk calculations and analyzing familial segregation data, ConsCal assigns numerical values to segregation power, aiding in variant classification.

Another challenge arises from allelism, where the observed phenotype significantly deviates from what’s described in existing literature, hinting at a distinct allelic disorder. In consanguineous populations, such instances often stem from the recessive nature of the identified variant compared to dominant ones reported for the same condition. This enrichment of homozygous variants makes pinpointing the culprit mutation even more challenging.

Further complicating matters, the co-inheritance of two or more genetic conditions within a single family can lead to blended phenotypes. Blended phenotypes are observed in non-consanguineous populations, but are observed more often in consanguineous populations. Their phenotypes can merge into a complex presentation, further obscuring the interpretation of individual variants. Deciphering the contributing variants behind such complicated presentations becomes particularly challenging when multiple genes converge on the same phenotype. Additionally, when causative variants for different conditions reside on the same haplotype (a run of homozygosity) and are co-inherited, the phenotype complexity intensifies.

Annually, hundreds of new genes are linked to human phenotypes. In consanguineous populations, where rare conditions are more common, interpreting these novel gene assertions becomes a significant hurdle, especially when the gene-disease association is yet to be established.

Finally, population-specific allele frequencies require careful consideration. In consanguineous communities, the default allele frequency (AF) cutoff of <0.001 used for rare recessive diseases can be ineffective. Unless identified as major founder mutations, such variants risk being filtered out, potentially masking their pathogenic roles. Furthermore, the presence of multi-variant homozygous pathogenic variants on the same allele, co-inherited and contributing to the disease phenotype, presents another diagnostic hurdle.

Pedigree-related factors can also introduce complexities. The inherent assumption of homozygosity in consanguineous families can lead to overlooking other potential causes, such as pathogenic variants of autosomal dominant or X-linked genes. Conversely, a variant might be wrongly dismissed because it lies outside shared autozygous regions within affected individuals.

Unravelling the mysteries of genetic variations in consanguineous families demands a careful approach that acknowledges these unique challenges. By employing specialized tools, adopting population-specific considerations, and meticulously analyzing pedigree data, we can gradually refine our understanding of variant interpretation in these populations, paving the way for accurate diagnoses and improved patient care.

To learn more about initiatives to close gaps of information, watch Dr Fowzan Alkuraya’s presentation to the ASHG Awards 2020.