Inflammatory breast cancer (IBC) is a rare and aggressive form of breast cancer, characterized by distinct clinicopathological features and a relatively high frequency in North African countries. While several studies have explored the genetic basis of breast cancer, limited research has looked into the specific genetic features of this aggressive form. This study aims to investigate the genetic factors associated with IBC in North Africa, particularly among Tunisian patients.Whole exome sequencing was performed for 13 patients with IBC. Clinicopathological data have been collected to assess the phenotype-genotype correlation. Both germline point mutations and copy number variations (CNVs) were analyzed. Genes and variants were prioritized through phenotype and genotype-driven approaches. Variants were filtered based on pathogenicity predictions and ACMG classification. A Gene-Disease association analysis was conducted using DisGeNET data and the VarElect online tool to select candidate genes most likely involved in disease onset. The predictive and prognostic values of the relevant genes were assessed using publicly available datasets.Our investigations revealed relevant genetic variants within established cancer predisposing genes, inflammatory pathways, and potential candidate predisposing genes, including BRCA2 c.1794_1798del, a novel mutation in RAD54L gene (c.1712T > C) and c.555_559del in IFNAR2 gene. CNVs in ABRAXAS1, XRCC2 and FANC genes were identified. We have also found that the high expression levels of RAD54L and MTHFR are correlated with good survival rates. The genetic makeup of IBC seems to be very heterogeneous. For the same patient, we have detected several relevant variants that might explain disease development and progression, and this was consistent with the family history of cancer observed in the investigated families.Our findings revealed a complex and heterogeneous genetic background of IBC in the Tunisian population that might contribute to disease susceptibility and impact disease prognosis. The genetic features of IBC presented in this study provide valuable insights into the molecular mechanisms underlying the disease offering not only a deeper understanding within the context of Tunisia but also shedding light on its relevance to other North African populations characterized by similar epidemiological and genetic features.