{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,12,12]],"date-time":"2025-12-12T13:48:05Z","timestamp":1765547285883,"version":"3.41.2"},"reference-count":98,"publisher":"Oxford University Press (OUP)","issue":"4","license":[{"start":{"date-parts":[[2024,7,22]],"date-time":"2024-07-22T00:00:00Z","timestamp":1721606400000},"content-version":"vor","delay-in-days":60,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100003977","name":"Israeli Science Foundation","doi-asserted-by":"crossref","award":["ISF 1466\/18","737\/23"],"award-info":[{"award-number":["ISF 1466\/18","737\/23"]}],"id":[{"id":"10.13039\/501100003977","id-type":"DOI","asserted-by":"crossref"}]},{"name":"SHEMESH","award":["3175006632"],"award-info":[{"award-number":["3175006632"]}]},{"DOI":"10.13039\/100001006","name":"Breast Cancer Research Foundation","doi-asserted-by":"publisher","id":[{"id":"10.13039\/100001006","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Robin Chambers Neustein Director of the Fuld Family Medical Genetic Institute"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2024,5,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Breast cancer (BC) is the most common malignancy affecting Western women today. It is estimated that as many as 10% of BC cases can be attributed to germline variants. However, the genetic basis of the majority of familial BC cases has yet to be identified. Discovering predisposing genes contributing to familial BC is challenging due to their presumed rarity, low penetrance, and complex biological mechanisms. Here, we focused on an analysis of rare missense variants in a cohort of 12 families of Middle Eastern origins characterized by a high incidence of BC cases. We devised a novel, high-throughput, variant analysis pipeline adapted for family studies, which aims to analyze variants at the protein level by employing state-of-the-art machine learning models and three-dimensional protein structural analysis. Using our pipeline, we analyzed 1218 rare missense variants that are shared between affected family members and classified 80 genes as candidate pathogenic. Among these genes, we found significant functional enrichment in peroxisomal and mitochondrial biological pathways which segregated across seven families in the study and covered diverse ethnic groups. We present multiple evidence that peroxisomal and mitochondrial pathways play an important, yet underappreciated, role in both germline BC predisposition and BC survival.<\/jats:p>","DOI":"10.1093\/bib\/bbae346","type":"journal-article","created":{"date-parts":[[2024,7,22]],"date-time":"2024-07-22T23:45:28Z","timestamp":1721691928000},"source":"Crossref","is-referenced-by-count":1,"title":["Discovering predisposing genes for hereditary breast cancer using deep learning"],"prefix":"10.1093","volume":"25","author":[{"given":"Gal","family":"Passi","sequence":"first","affiliation":[{"name":"The Rachel and Selim Benin School of Computer Science and Engineering , The Hebrew University of Jerusalem, Jerusalem 9190401, Israel"}]},{"given":"Sari","family":"Lieberman","sequence":"additional","affiliation":[{"name":"The Fuld Family Medical Genetics Institute, Shaare Zedek Medical Center 12 Bayit St. , Jerusalem 9103101 , Israel"},{"name":"The Eisenberg R&D Authority , Shaare Zedek Medical Center, 12 Bayit St., Jerusalem 9103101, Israel"},{"name":"Faculty of Medicine, The Hebrew University of Jerusalem , Ein Kerem PO Box 12271 Jerusalem 9112102 , Israel"}]},{"given":"Fouad","family":"Zahdeh","sequence":"additional","affiliation":[{"name":"The Fuld Family Medical Genetics Institute, Shaare Zedek Medical Center 12 Bayit St. , Jerusalem 9103101 , Israel"},{"name":"The Eisenberg R&D Authority , Shaare Zedek Medical Center, 12 Bayit St., Jerusalem 9103101, Israel"}]},{"given":"Omer","family":"Murik","sequence":"additional","affiliation":[{"name":"The Fuld Family Medical Genetics Institute, Shaare Zedek Medical Center 12 Bayit St. , Jerusalem 9103101 , Israel"},{"name":"The Eisenberg R&D Authority , Shaare Zedek Medical Center, 12 Bayit St., Jerusalem 9103101, Israel"}]},{"given":"Paul","family":"Renbaum","sequence":"additional","affiliation":[{"name":"The Fuld Family Medical Genetics Institute, Shaare Zedek Medical Center 12 Bayit St. , Jerusalem 9103101 , Israel"},{"name":"The Eisenberg R&D Authority , Shaare Zedek Medical Center, 12 Bayit St., Jerusalem 9103101, Israel"}]},{"given":"Rachel","family":"Beeri","sequence":"additional","affiliation":[{"name":"The Fuld Family Medical Genetics Institute, Shaare Zedek Medical Center 12 Bayit St. , Jerusalem 9103101 , Israel"},{"name":"The Eisenberg R&D Authority , Shaare Zedek Medical Center, 12 Bayit St., Jerusalem 9103101, Israel"}]},{"given":"Michal","family":"Linial","sequence":"additional","affiliation":[{"name":"Department of Biological Chemistry , Institute of Life Sciences, The Hebrew University of Jerusalem, Edmond J. Safra Campus, Givat Ram, Jerusalem 91904, Israel"}]},{"given":"Dalit","family":"May","sequence":"additional","affiliation":[{"name":"The Fuld Family Medical Genetics Institute, Shaare Zedek Medical Center 12 Bayit St. , Jerusalem 9103101 , Israel"},{"name":"The Eisenberg R&D Authority , Shaare Zedek Medical Center, 12 Bayit St., Jerusalem 9103101, Israel"},{"name":"Clalit Health Services , Jerusalem , Israel"}]},{"given":"Ephrat","family":"Levy-Lahad","sequence":"additional","affiliation":[{"name":"The Fuld Family Medical Genetics Institute, Shaare Zedek Medical Center 12 Bayit St. , Jerusalem 9103101 , Israel"},{"name":"The Eisenberg R&D Authority , Shaare Zedek Medical Center, 12 Bayit St., Jerusalem 9103101, Israel"},{"name":"Faculty of Medicine, The Hebrew University of Jerusalem , Ein Kerem PO Box 12271 Jerusalem 9112102 , Israel"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0480-0438","authenticated-orcid":false,"given":"Dina","family":"Schneidman-Duhovny","sequence":"additional","affiliation":[{"name":"The Rachel and Selim Benin School of Computer Science and Engineering , The Hebrew University of Jerusalem, Jerusalem 9190401, Israel"}]}],"member":"286","published-online":{"date-parts":[[2024,7,22]]},"reference":[{"key":"2024072223451103000_ref1","doi-asserted-by":"crossref","first-page":"465","DOI":"10.1136\/jmedgenet-2015-103672","article-title":"Prevalence of BRCA1\/2 germline mutations in 21 401 families with breast and ovarian cancer","volume":"53","author":"Kast","year":"2016","journal-title":"J Med Genet"},{"key":"2024072223451103000_ref2","doi-asserted-by":"crossref","first-page":"1291","DOI":"10.1093\/annonc\/mdv022","article-title":"Genetics of breast cancer: a topic in evolution","volume":"26","author":"Shiovitz","year":"2015","journal-title":"Ann 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