Understanding genetic epidemiology and population disparities of inherited blood cancer syndromes from integrative analysis of population genomics datasets

Abstract

Interpopulation differences in prevalence have been well documented for a number of diseases including genetic diseases. The availability of population scale datasets and well-annotated variant resources would therefore offer a new opportunity to understand the genetic factors linked with such population differences or disparities. In the present manuscript, we evaluated the allele frequencies of genetic variants in inherited blood cancer syndromes in population genomes to understand whether they could provide an insight into these population disparities. We analysed 10 inherited disorders, encompassing 20 different genes. Pathogenic variants were systematically collected, and reclassified using the ACMG & AMP guidelines. Variant prevalence was studied using the Genome Aggregation Database (gnomAD) database, which provided a unique population template to understand prevalence across major global populations. Our analysis highlights high-confidence Pathogenic variants that are significantly enriched across specific subpopulations. To the best of our knowledge, this is the first and comprehensive analysis of genetic variants in inherited blood cancer syndromes in global populations and one of the first to suggest allele specific disparities across global populations.

Keywords

• Precision medicine
• Germline
• Pediatric leukemia
• Inherited susceptibility
• Epidemiology
• Genetic testing