{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,2]],"date-time":"2026-09-02T11:29:19Z","timestamp":1788348559071,"version":"build-2803163510"},"reference-count":29,"publisher":"Oxford University Press (OUP)","issue":"6","license":[{"start":{"date-parts":[[2026,4,4]],"date-time":"2026-04-04T00:00:00Z","timestamp":1775260800000},"content-version":"vor","delay-in-days":93,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,3,23]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Retinoblastoma (RB) is typically associated with highly penetrant pathogenic sequence variants (PSVs) in the RB1 gene; however, some families exhibit low penetrance RB (LPRB). We aimed to determine the penetrance rate and identify genetic and clinical characteristics of LPRB. To that end two cohorts were analyzed: 250 genetically confirmed LPRB cases identified through systematic literature review and 78 classical germline RB (CGRB) from three international centers- Thailand, Korea, and Israel. Penetrance rate was estimated as the proportion of affected individuals among RB1 PSV carriers. Multivariate models assessed parent-of-origin effects and predictors of penetrance. PSVs were annotated with Combined Annotation Dependent Depletion (CADD) scores and mapped to pRB structural domains. LPRB penetrance ranged from 50% (125\/250, non-age-adjusted, CI [43.8%\u201356.2%]) to 64% (125\/196, age-adjusted, CI [56.8%\u201370.2%]). Paternal inheritance of RB1 PSV was associated with a significantly increased risk of LPRB in offspring (OR\u2009=\u20096.24; P\u2009&amp;lt;\u20090.0001). Clinically, LPRB were significantly more likely than CGRB to present with unilateral disease (OR\u2009=\u20099.3, P\u2009&amp;lt;\u20090.0001), diagnosed at an older age (13 Vs 6.5\u00a0months, P\u2009=\u20090.01), and affect males (OR\u2009=\u20092.4, P\u2009=\u20090.03). LPRB-associated PSVs showed lower CADD scores (OR\u2009=\u20091.5; P\u2009=\u20090.0008), indicating lower predicted pathogenicity, and were enriched in pRB\u2019s N- or C-terminal domains (OR\u2009=\u20093.2; P\u2009=\u20090.007), consistent with hypomorphic effects. In conclusion, LPRB shows a 50\u201364% penetrance rate, more likely to be paternally inherited, have unilateral presentation, and associated with hypomorphic RB1 PSVs in the terminal pRB regions. These findings support retitling \u2018low penetrance RB\u2019 to \u2018medium penetrance RB\u2019.<\/jats:p>","DOI":"10.1093\/hmg\/ddag026","type":"journal-article","created":{"date-parts":[[2026,3,18]],"date-time":"2026-03-18T12:50:08Z","timestamp":1773838208000},"source":"Crossref","is-referenced-by-count":1,"title":["Revisiting low penetrance retinoblastoma: an integrated clinical, genetic, and bioinformatic analysis"],"prefix":"10.1093","volume":"35","author":[{"given":"Eden","family":"Avnat","sequence":"first","affiliation":[{"name":"Gray Faculty of Medicine, Tel Aviv University , Tel Aviv 69978 ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Guy","family":"Shapira","sequence":"additional","affiliation":[{"name":"Gray Faculty of Medicine, Tel Aviv University , Tel Aviv 69978 ,","place":["Israel"]},{"name":"Edmond J. Safra Center for Bioinformatics, Tel Aviv University , Tel Aviv 69978 ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yael","family":"Lustig","sequence":"additional","affiliation":[{"name":"The Goldschleger Eye Institute , Sheba Medical Center, Tel Hashomer, Ramat Gan 62521 ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jonathan","family":"Citrin","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, Hebrew University of Jerusalem , Jerusalem 9112102 ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Duangnate","family":"Rojanaporn","sequence":"additional","affiliation":[{"name":"Department of Ophthalmology, Faculty of Medicine, Ramathibodi Hospital, Mahidol University , 270 Rama VI Road, Thung Phaya Thai, Ratchathewi, Bangkok 10400 ,","place":["Thailand"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rossukon","family":"Kaewkhaw","sequence":"additional","affiliation":[{"name":"Chakri Naruebodindra Medical Institute, Faculty of Medicine Ramathibodi Hospital , 111 Moo 14, Tambon Bang Pla, Amphoe Bang Phli, Samut Prakan 10540,","place":["Thailand"]},{"name":"Program in Translational Medicine, Faculty of Medicine Ramathibodi Hospital, Mahidol University , 270 Rama VI Road, Thung Phaya Thai, Ratchathewi, Bangkok 10400 ,","place":["Thailand"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dong Hyun","family":"Jo","sequence":"additional","affiliation":[{"name":"Department of Anatomy and Cell Biology, Seoul National University College of Medicine , 103 Daehak-ro, Jongno-gu, Seoul 03080 ,","place":["Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeong Hun","family":"Kim","sequence":"additional","affiliation":[{"name":"Department of Biomedical Sciences and Ophthalmology, Seoul National University College of Medicine , 103 Daehak-ro, Jongno-gu, Seoul 03080 ,","place":["Republic of Korea"]},{"name":"Global Excellence Center for Gene and Cell Therapy, Seoul Narional University Hospital , 103 Daehak-ro, Jongno-gu, Seoul 03080 ,","place":["Republic of Korea"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Noam","family":"Shomron","sequence":"additional","affiliation":[{"name":"Gray Faculty of Medicine, Tel Aviv University , Tel Aviv 69978 ,","place":["Israel"]},{"name":"Edmond J. Safra Center for Bioinformatics, Tel Aviv University , Tel Aviv 69978 ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6745-1733","authenticated-orcid":false,"given":"Eitan","family":"Friedman","sequence":"additional","affiliation":[{"name":"Gray Faculty of Medicine, Tel Aviv University , Tel Aviv 69978 ,","place":["Israel"]},{"name":"The Meirav High Risk Clinic, Chaim Sheba Medical Center, Tel-Hashomer , Ramat Gan 52621 ,","place":["Israel"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ido Didi","family":"Fabian","sequence":"additional","affiliation":[{"name":"The Goldschleger Eye Institute , Sheba Medical Center, Tel Hashomer, Ramat Gan 62521 ,","place":["Israel"]},{"name":"International Centre for Eye Health, London School of Hygiene & Tropical Medicine , Keppel Street, London , WC1E 7HT,","place":["United 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