The Identification by Exome Sequencing of Candidate Genes in -Negative Tunisian Patients at a High Risk of Hereditary Breast/Ovarian Cancer.

(1) Background: Germline variants in genes explain about 20% of hereditary breast/ovarian cancer (HBOC) cases. In the present paper, we aim to identify genetic determinants in -negative families from the South of Tunisia. (2) Methods: Exome Sequencing (ES) was performed on the lymphocyte DNA of patients negative for mutations from each Tunisian family with a high risk of HBOC. (3) Results: We focus on the canonical genes associated with HBOC and identified missense variants in DNA damage response genes, such as , , and ; however, no variants in , , and genes were found. To identify novel candidate genes, we selected variants harboring a loss of function and identified 17 stop-gain and 11 frameshift variants in genes not commonly known to be predisposed to HBOC. Then, we focus on rare and high-impact genes shared by at least 3 unrelated patients from each family and selected 16 gene variants. Through combined data analysis from MCODE with gene ontology and KEGG pathways, a short list of eight candidate genes (, , , , , , , and ) was created. The impact of the 24 selected genes on survival was analyzed using the TCGA data resulting in a selection of five candidate genes (, , , , and that showed a significant association with survival. (4) Conclusions: We identify novel candidate genes predisposed to HBOC that need to be validated in larger cohorts and investigated by analyzing the co-segregation of selected variants in affected families and the locus-specific loss of heterozygosity to highlight their relevance for HBOC risk.