{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T13:45:50Z","timestamp":1770817550587,"version":"3.50.1"},"reference-count":20,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T00:00:00Z","timestamp":1770768000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Early-onset breast cancer (EOBC) is disproportionately common in Saudi Arabia, where women present nearly a decade earlier than in Western countries, suggesting unique inherited susceptibility. While BRCA1\/2 explain part of the hereditary risk, the contribution of rare coding variants in Arab EOBC remains unclear. Whole-exome sequencing was performed on germline DNA from 102 unrelated Saudi EOBC patients and 1395 cancer-free controls recruited from the same national Saudi cohort. Rare variants were defined by stringent frequency and quality thresholds and classified as rare loss-of-function (RLOF) or rare predicted damaging variants (RPDVs). Gene-level case\u2013control analyses were conducted using burden tests, with exome-wide significance set at p &lt; 2.5 \u00d7 10\u22126. RLOF variants in BRCA1 (6.9% of EOBC vs. 0.14% of controls; OR = 51.3; p &lt; 1.0 \u00d7 10\u221210) and RPDVs in TP53 (4.9% vs. 0.36%; OR = 14.3; p = 5.39 \u00d7 10\u22128) demonstrated strong associations. Sequence Kernel Association Test (SKAT) analysis identified NOTCH4 and OR12D3 and reinforced burden-based significance in GUCY2F, FRMPD3, and SHROOM2. No enriched signaling pathway emerged, indicating heterogeneous rare-variant mechanisms. This first germline exome-wide rare-variant association study in Saudi EOBC identifies substantial enrichment driven by BRCA1, TP53, and additional candidate genes, supporting population-specific genetic risk evaluation and the need for replication in larger Arab cohorts.<\/jats:p>","DOI":"10.3390\/ijms27041732","type":"journal-article","created":{"date-parts":[[2026,2,11]],"date-time":"2026-02-11T11:13:15Z","timestamp":1770808395000},"page":"1732","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Exome-Wide Association Analysis Identifies Rare Germline Susceptibility Variants in Early-Onset Breast Cancer Among Saudi Women"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6853-1049","authenticated-orcid":false,"given":"Rong","family":"Bu","sequence":"first","affiliation":[{"name":"Genomic Analytics, Research and Innovation, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5634-5030","authenticated-orcid":false,"given":"Kaleem","family":"Iqbal","sequence":"additional","affiliation":[{"name":"Genomic Analytics, Research and Innovation, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Sandeep Kumar","family":"Parvathareddy","sequence":"additional","affiliation":[{"name":"Human Cancer Genomic Research, Research and Innovation, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8091-5280","authenticated-orcid":false,"given":"Saud","family":"Azam","sequence":"additional","affiliation":[{"name":"Human Cancer Genomic Research, Research and Innovation, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4026-8987","authenticated-orcid":false,"given":"Zeeshan","family":"Qadri","sequence":"additional","affiliation":[{"name":"Human Cancer Genomic Research, Research and Innovation, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eman A.","family":"Abdul Razzaq","sequence":"additional","affiliation":[{"name":"Translational Oncology Research, Research and Innovation, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Fouad","family":"Al-Dayel","sequence":"additional","affiliation":[{"name":"Anatomic Pathology Department, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2162-6857","authenticated-orcid":false,"given":"Abdul K.","family":"Siraj","sequence":"additional","affiliation":[{"name":"Translational Oncology Research, Research and Innovation, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4126-3419","authenticated-orcid":false,"given":"Khawla S.","family":"Al-Kuraya","sequence":"additional","affiliation":[{"name":"Human Cancer Genomic Research, Research and Innovation, King Faisal Specialist Hospital and Research Centre, Riyadh 11211, Saudi Arabia"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,2,11]]},"reference":[{"key":"ref_1","first-page":"209","article-title":"Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries","volume":"71","author":"Sung","year":"2021","journal-title":"CA Cancer J. 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