{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,17]],"date-time":"2026-07-17T02:16:06Z","timestamp":1784254566058,"version":"3.55.0"},"reference-count":47,"publisher":"American Society for Clinical Investigation","issue":"4","license":[{"start":{"date-parts":[[2025,2,24]],"date-time":"2025-02-24T00:00:00Z","timestamp":1740355200000},"content-version":"vor","delay-in-days":60,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"crossref","award":["K08EY033789"],"award-info":[{"award-number":["K08EY033789"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100001130","name":"Gerber Foundation","doi-asserted-by":"crossref","award":["National grant"],"award-info":[{"award-number":["National grant"]}],"id":[{"id":"10.13039\/100001130","id-type":"DOI","asserted-by":"crossref"}]},{"DOI":"10.13039\/100001818","name":"Research to Prevent Blindness","doi-asserted-by":"crossref","award":["Institutional Grant"],"award-info":[{"award-number":["Institutional Grant"]}],"id":[{"id":"10.13039\/100001818","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2025,2,24]]},"abstract":"<jats:sec>\n                    <jats:title>BACKGROUND<\/jats:title>\n                    <jats:p>Current clinical sequencing methods cannot effectively detect DNA methylation and allele-specific variation to provide parent-of-origin information from the proband alone. Parent-of-origin effects can lead to differential disease, and the inability to assign parent of origin in de novo cases limits prognostication in the majority of affected individuals with retinoblastoma, a hereditary cancer with suspected parent-of-origin effects.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>METHODS<\/jats:title>\n                    <jats:p>\n                      To directly assign parent of origin in patients with retinoblastoma, we extracted genomic DNA from blood samples for sequencing using a programmable, targeted, single-molecule, long-read DNA genomic and epigenomic approach. This allowed germline variant calling and simultaneous haplotype-resolved CpG methylation in participants with familial (\n                      <jats:italic>n<\/jats:italic>\n                      = 7) and de novo (\n                      <jats:italic>n<\/jats:italic>\n                      = 9) retinoblastoma.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>RESULTS<\/jats:title>\n                    <jats:p>\n                      Targeted long-read sequencing allowed phasing genomic variation with a differentially methylated region in intron 2 of the retinoblastoma gene to confirm parent of origin in known familial samples. This approach allowed us to directly assign parent of origin in simple and complex de novo cases from the proband alone. The ability to assign parent of origin in all retinoblastoma cases showed that harboring disease-causing variants on the paternally inherited allele, whether arising familially or de novo, was associated with more advanced cancer staging at presentation and significantly greater risk of chemotherapy failure (\n                      <jats:italic>P<\/jats:italic>\n                      = 0.002).\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>CONCLUSION<\/jats:title>\n                    <jats:p>This study demonstrates the diagnostic potential of multiomic long-read profiling to unveil the parent-of-origin effect in hereditary cancer. The approach in this work will be instrumental in assigning parent of origin to other genetic diseases using local and distant imprinting signals in the genome.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>FUNDING<\/jats:title>\n                    <jats:p>National Eye Institute, NIH; Gerber Foundation; Research to Prevent Blindness; Angie Karalis Johnson Fund; Dawn\u2019s Light Foundation; and Mark J. Daily, MD Research Fund<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1172\/jci.insight.188216","type":"journal-article","created":{"date-parts":[[2024,12,26]],"date-time":"2024-12-26T12:00:26Z","timestamp":1735214426000},"source":"Crossref","is-referenced-by-count":3,"title":["Prognostic importance of direct assignment of parent of origin via long-read genome and epigenome sequencing in retinoblastoma"],"prefix":"10.1172","volume":"10","author":[{"given":"Andrew W.","family":"Stacey","sequence":"first","affiliation":[{"name":"Department of Ophthalmology and Roger and Angie Karalis Johnson Retina Center, University of Washington, Seattle, Washington, USA."},{"name":"Division of Ophthalmology, Seattle Children\u2019s Hospital, Seattle, Washington, USA."},{"name":"Fred Hutch Cancer Consortium, Seattle, Washington, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kenji","family":"Nakamichi","sequence":"additional","affiliation":[{"name":"Department of 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