Investigation of germline variants in Bahraini women with breast cancer using next-generation sequencing based-multigene panel.

Germline variants in BRCA1 and BRCA2 (BRCA1/2) genes are the most common cause of hereditary breast cancer. However, a significant number of cases are not linked to these two genes and additional high-, moderate- and low-penetrance genes have been identified in breast cancer. The advent of next-generation sequencing (NGS) allowed simultaneous sequencing of multiple cancer-susceptibility genes and prompted research in this field. So far, cancer-predisposition genes other than BRCA1/2 have not been studied in the population of Bahrain. We performed a targeted NGS using a multi-panel covering 180 genes associated with cancer predisposition to investigate the spectrum and frequency of germline variants in 54 women with a positive personal and/or family history of breast cancer. Sequencing analysis revealed germline variants in 29 (53.7%) patients. Five pathogenic/likely pathogenic variants in four DNA repair pathway-related genes were identified in five unrelated patients (9.3%). Two BRCA1 variants, namely the missense variant c.287A>G (p.Asp96Gly) and the truncating variant c.1066C>T (p.Gln356Ter), were detected in two patients (3.7%). Three variants in non-BRCA1/2 genes were detected in three patients (1.85% each) with a strong family history of breast cancer. These included a monoallelic missense variant c.1187G>A (p.Gly396Asp) in MUTYH gene, and two truncating variants namely c.3343C>T (p.Arg1115Ter) in MLH3 gene and c.1826G>A (p.Trp609Ter) in PMS1 gene. Other variants of uncertain significance (VUS) were also detected, and some of them were found together with the deleterious variants. In this first application of NGS-based multigene testing in Bahraini women with breast cancer, we show that multigene testing can yield additional genomic information on low-penetrance genes, although the clinical significance of these genes has not been fully appreciated yet. Our findings also provide valuable epidemiological information for future studies and highlight the importance of genetic testing, and an NGS-based multigene analysis may be applied supplementary to traditional genetic counseling.

Demographic and Viral-Genetic Analyses of COVID-19 Severity in Bahrain Identify Local Risk Factors and a Protective Effect of Polymerase Mutations.

A multitude of demographic, health, and genetic factors are associated with the risk of developing severe COVID-19 following infection by the SARS-CoV-2. There is a need to perform studies across human societies and to investigate the full spectrum of genetic variation of the virus. Using data from 869 COVID-19 patients in Bahrain between March 2020 and March 2021, we analyzed paired viral sequencing and non-genetic host data to understand host and viral determinants of severe COVID-19. We estimated the effects of demographic variables specific to the Bahrain population and found that the impact of health factors are largely consistent with other populations. To extend beyond the common variants of concern in the Spike protein analyzed by previous studies, we used a viral burden approach and detected a protective effect of low-frequency missense viral mutations in the RNA-dependent RNA polymerase (Pol) gene on disease severity. Our results contribute to the survey of severe COVID-19 in diverse populations and highlight the benefits of studying rare viral mutations.