{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,7,14]],"date-time":"2026-07-14T06:25:45Z","timestamp":1784010345298,"version":"3.55.0"},"posted":{"date-parts":[[2026,6,24]]},"group-title":"Genetic and Genomic Medicine","reference-count":0,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,6,24]],"date-time":"2026-06-24T00:00:00Z","timestamp":1782259200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,6,24]]},"abstract":"<jats:p>Rare diseases collectively affect 1 in 10 individuals, yet current genetic testing fails to identify a causal variant for most cases. At present, cytogenetic methods and\/or sequencing approaches such as exome (ES) or short-read genome sequencing (srGS) represent the state-of-the-art for comprehensive clinical discovery of sequence and structural variants (SVs), including copy number variants, balanced SVs, complex SVs, and tandem repeats (TRs). Recently, long-read genome sequencing (lrGS), coupled with multiomics data, has presented great promise to resolve variation in genomic regions recalcitrant to characterization by srGS such as highly repetitive simple repeat sequences and segmental duplications. However, there are few guidelines to enable clinical interpretation of genetic variation in these highly repetitive genomic regions, and the enthusiasm of the field in adopting lrGS has made it difficult to assess the true added diagnostic yield of this technology due to widely variable and inconsistently applied analytic pipelines and variable degrees of pre-screening by ES or srGS. Here, we investigated the contribution of SVs to rare diseases using srGS as a front-line strategy when paired with highly sensitive SV discovery and evaluate the added diagnostic yield of incorporating lrGS for a subset of cases. Our srGS analysis encompassed 1,462 families (3,450 individuals) recruited through the Broad Institute Center for Mendelian Genetics and the Genomics Research to Elucidate the Genetics of Rare Diseases (GREGoR) programs. Diagnostic SVs were identified in 5.4% of cases (79\/1,462), of which 80% were uniquely detectable by srGS compared to standard cytogenetic techniques. For 96 families (including 10 families with a heterozygous variant observed in a known recessive gene of clinical relevance), we performed lrGS with methylation profiling, as well as long-read transcriptomic analyses in a subset of 20 trios. Analyses with lrGS yielded over 25,000 SVs per genome, 63% of which were not captured by srGS, along with an additional ~200 rare SNV\/indels per genome not previously captured and 12 differentially methylated regions per genome. Among these, we identified only one diagnostic variant not interpreted by srGS, an apparently mosaic de novo SNV in CASK that was absent in the srGS callset due to allelic imbalance. No new diagnoses were supported by long-read transcriptomics or episignatures. In this well characterized rare disease cohort, the added diagnostic yield was thus 1.04% (1\/96 families). Following a systematic literature review of prior lrGS studies, we find that most reported diagnoses were detectable by srGS and that our added diagnostic yield is consistent with those prior studies. These studies emphasize the significant impact of comprehensive SV discovery in rare disease cases and further demonstrate the power for increased discovery of novel genomic variation and episignatures from lrGS. Nonetheless, they also serve to temper expectations of dramatic diagnostic advances in rare disease patients until there is more extensive annotation of the functional and clinical impact of all coding and noncoding variation uniquely accessible to lrGS with extensive reference databases spanning highly repetitive genomic sequencing that could be enabled by this transformative technology.<\/jats:p>","DOI":"10.64898\/2026.06.22.26356238","type":"posted-content","created":{"date-parts":[[2026,6,25]],"date-time":"2026-06-25T02:20:13Z","timestamp":1782354013000},"source":"Crossref","is-referenced-by-count":1,"title":["Structural variant discovery and diagnostic impact in rare diseases from short-read and long-read sequencing"],"prefix":"10.64898","author":[{"given":"Alba","family":"Sanchis-Juan","sequence":"first","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical S;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yulia","family":"Mostovoy","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical S;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah L","family":"Stenton","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; The Manton Center for Orphan Disease Research, Division of Genetics and Genom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8709-9351","authenticated-orcid":false,"given":"Vijay S","family":"Ganesh","sequence":"additional","affiliation":[{"name":"Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9898-9109","authenticated-orcid":false,"given":"Ben","family":"Weisburd","sequence":"additional","affiliation":[{"name":"Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alex","family":"Yenkin","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Division of Medical Sciences, Harvard Medical School, Boston, MA, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nehir E","family":"Kurtas","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical S;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xuefang","family":"Zhao","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical S;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eren","family":"Shin","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical S;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip M","family":"Boone","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical S;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hang","family":"Su","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4513-4630","authenticated-orcid":false,"given":"Arthur S","family":"Lee","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical S;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rachita","family":"Yadav","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical S;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kirsten","family":"Allan","sequence":"additional","affiliation":[{"name":"Victorian Clinical Genetics Services, Royal Children's Hospital, Melbourne, Victoria, Australia; Department of Paediatrics, University of Melbourne, Melbourne, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emanuela","family":"Argilli","sequence":"additional","affiliation":[{"name":"Department of Neurology, University of California, San Francisco, CA, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christina","family":"Austin-Tse","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brenda J","family":"Barry","sequence":"additional","affiliation":[{"name":"Department of Neurology, Boston Children's Hospital, Boston, MA, USA; F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA; Howard Hughes Medical Institute, Chevy Chase, MD, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4616-9234","authenticated-orcid":false,"given":"Samantha","family":"Baxter","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan H","family":"Beggs","sequence":"additional","affiliation":[{"name":"Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; The Manton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Harv;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katrina M","family":"Bell","sequence":"additional","affiliation":[{"name":"Victorian Clinical Genetics Services, Royal Children's Hospital, Melbourne, Victoria, Australia; Murdoch Children's Research Institute, Melbourne, Victoria, Australia;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Benjamin","family":"Blankenmeister","sequence":"additional","affiliation":[{"name":"Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5930-2324","authenticated-orcid":false,"given":"Carsten G","family":"B\u00f6nnemann","sequence":"additional","affiliation":[{"name":"Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7371-0340","authenticated-orcid":false,"given":"Catherine A","family":"Brownstein","sequence":"additional","affiliation":[{"name":"The Manton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Harvard Medical School, Boston, MA USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kinga M","family":"Bujakowska","sequence":"additional","affiliation":[{"name":"Ocular Genomics Institute, Mass Eye and Ear, Harvard Medical School, Boston, MA, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth","family":"Carbonell","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra T","family":"Cooper","sequence":"additional","affiliation":[{"name":"Kids Neuroscience Centre, Kids Research, The Children's Hospital at Westmead, Sydney, Australia; The Children's Medical Research Institute, Sydney, Australia; School of Medical Sciences, Faculty of Medicine and Health, University of Sydney, Sydney, Austra;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura E","family":"Covill","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; The Manton Center for Orphan Disease Research, Division of Genetics and Genom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephanie","family":"DiTroia","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; The Manton Center for Orphan Disease Research, Division of Genetics and Genom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sandra","family":"Donkervoort","sequence":"additional","affiliation":[{"name":"Neuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elizabeth C","family":"Engle","sequence":"additional","affiliation":[{"name":"Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Neurology, Boston Children's Hospital, Boston, MA, USA; F.M. 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Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA; Departme;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Akanksha","family":"Khorgade","sequence":"additional","affiliation":[{"name":"Genomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gabrielle","family":"Lemire","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; The Manton Center for Orphan Disease Research, Division of Genetics and Genom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"Liau","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; Department of Neurology, Massachusetts General Hospital and Harvard Medical S;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jialan","family":"Ma","sequence":"additional","affiliation":[{"name":"Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jill A","family":"Madden","sequence":"additional","affiliation":[{"name":"The Manton Center for Orphan Disease Research, Division of Genetics and Genomics, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA; Harvard Medical School, Boston, MA USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brian","family":"Mangilog","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Brandy M","family":"McNulty","sequence":"additional","affiliation":[{"name":"Department of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, CA, USA; UC Santa Cruz Genomics Institute, University of California Santa Cruz, Santa Cruz, CA, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olfa","family":"Messaoud","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; Program in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA; The Manton Center for Orphan Disease Research, Division of Genetics and Genom;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9839-4030","authenticated-orcid":false,"given":"Shloka","family":"Negi","sequence":"additional","affiliation":[{"name":"UC Santa Cruz Genomics Institute, University of California Santa Cruz, Santa Cruz, CA, USA;"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Emily","family":"O'Heir","sequence":"additional","affiliation":[{"name":"Center for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA; 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