{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,9,15]],"date-time":"2026-09-15T13:05:43Z","timestamp":1789477543180,"version":"build-2803163510"},"posted":{"date-parts":[[2026,9,10]]},"group-title":"Genetic and Genomic Medicine","reference-count":69,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,9,10]],"date-time":"2026-09-10T00:00:00Z","timestamp":1788998400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"crossref","award":["U01HG011745"],"award-info":[{"award-number":["U01HG011745"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"crossref"}]},{"name":"GREGoR Data Coordinating Center","award":["U24HG011746"],"award-info":[{"award-number":["U24HG011746"]}]},{"DOI":"10.13039\/100000053","name":"National Eye Institute","doi-asserted-by":"crossref","award":["R01EY035717"],"award-info":[{"award-number":["R01EY035717"]}],"id":[{"id":"10.13039\/100000053","id-type":"DOI","asserted-by":"crossref"}]},{"name":"MEEI core support","award":["P30EY014104"],"award-info":[{"award-number":["P30EY014104"]}]},{"name":"Iraty Award 2023"},{"name":"Lions Foundation"},{"id":[{"id":"https:\/\/ror.org\/04drjs621","id-type":"ROR","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,9,10]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>A growing body of work has highlighted advantages of long-read genome sequencing (LR-GS) over short-read genome sequencing (SR-GS) with regards to the detection and interpretation of pathogenic variants. However, the incremental diagnostic yield of LR-GS over SR-GS for patients with suspected Mendelian conditions has not been systematically characterized.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We performed LR-GS on 144 cases that previously had undergone SR-GS through the Pediatric Mendelian Genomics Research Center at the University of California, Irvine (PMGRC-UCI, a founding center of the GREGoR Consortium), of which 107 remained undiagnosed after SR-GS.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Results<\/jats:title>\n                  <jats:p>\n                    We identified new molecular diagnoses in 13 cases, five of which could not have been detected with SR-GS, corresponding to an incremental diagnostic yield of 4.7%. These five diagnoses leveraged distinct capabilities of LR-GS: the detection of variants in short-read \u201cdark\u201d regions, the detection of structural variants and tandem repeat expansions, and the identification of\n                    <jats:italic>de novo<\/jats:italic>\n                    variants using only one biological parent. In two of these five cases, confirmation of the diagnosis also relied critically on identifying aberrant transcript production via RNA-seq, while in one other case LR-GS-based CpG methylation profiling further supported the diagnosis through detection of abnormal methylation at episignature-associated CpGs.\n                  <\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Conclusions<\/jats:title>\n                  <jats:p>In this paired comparison of LR-GS and SR-GS, LR-GS provided an incremental diagnostic yield of 4.7% among cases that remained undiagnosed after SR-GS. Together, our findings demonstrate that LR-GS can resolve a meaningful subset of cases beyond the reach of SR-GS while simultaneously expanding the range of genomic and epigenomic mechanisms accessible to a single sequencing assay.<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.09.09.26362331","type":"posted-content","created":{"date-parts":[[2026,9,11]],"date-time":"2026-09-11T16:10:14Z","timestamp":1789143014000},"source":"Crossref","is-referenced-by-count":0,"title":["Yield of Long-Read Genome Sequencing for Rare Disease Diagnosis in Short-Read Genome Negative Cases"],"prefix":"10.64898","author":[{"given":"Georgia","family":"Pitsava","sequence":"first","affiliation":[{"name":"Institute for Clinical and Translational Science, University of California, Irvine, CA, USA"},{"name":"Ambry Genetics, Aliso Viejo, CA, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Krista","family":"Bluske","sequence":"additional","affiliation":[{"name":"Ambry Genetics, 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