Evidence map›Paper›PMID 42396270›Full record

ArticlemedRxiv : the preprint server for health sciences2026

Structural variant discovery and diagnostic impact in rare diseases from short-read and long-read sequencing.

Alba Sanchis-Juan, Yulia Mostovoy, Sarah L Stenton, Vijay S Ganesh, Ben Weisburd, Alex Yenkin, Nehir E Kurtas, Xuefang Zhao, Eren Shin, Philip M Boone and 76 more

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Article in medRxiv : the preprint server for health sciences, 2026. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Not yet cited in PubMed.

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1 · What the graph read from it

What it found

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The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

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3 · Its place in the literature

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4 · The record

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5 · Who and what money

Authors and funding

86 authors.

Alba Sanchis-JuanCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Yulia MostovoyCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Sarah L StentonCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Vijay S GaneshProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID 0000-0002-8709-9351
Ben WeisburdProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID 0000-0001-9898-9109
Alex YenkinCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Nehir E KurtasCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Xuefang ZhaoCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Eren ShinCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Philip M BooneCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Hang SuCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Arthur S LeeCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.ORCID 0000-0002-4513-4630
Rachita YadavCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Kirsten AllanVictorian Clinical Genetics Services, Royal Children's Hospital, Melbourne, Victoria, Australia.
Emanuela ArgilliDepartment of Neurology, University of California, San Francisco, CA, USA.
Christina Austin-TseCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Brenda J BarryDepartment of Neurology, Boston Children's Hospital, Boston, MA, USA; F.M. Kirby Neurobiology Center, Boston Children's Hospital, Boston, MA, USA.
Samantha BaxterCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.ORCID 0000-0003-4616-9234
Alan H BeggsProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Katrina M BellVictorian Clinical Genetics Services, Royal Children's Hospital, Melbourne, Victoria, Australia.
Benjamin BlankenmeisterProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Carsten G BönnemannNeuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.ORCID 0000-0002-5930-2324
Catherine A BrownsteinThe 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.ORCID 0000-0002-7371-0340
Kinga M BujakowskaOcular Genomics Institute, Mass Eye and Ear, Harvard Medical School, Boston, MA, USA.
Elizabeth CarbonellCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Sandra T CooperKids 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, Australia.
Laura E CovillCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Stephanie DiTroiaCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Sandra DonkervoortNeuromuscular and Neurogenetic Disorders of Childhood Section, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, Maryland, USA.
Elizabeth C EngleProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Lyndon GallacherVictorian Clinical Genetics Services, Royal Children's Hospital, Melbourne, Victoria, Australia.
Casie A GenettiThe 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.
Joseph G GleesonDepartment of Neurosciences, University of California, San Diego, La Jolla, CA, USA; Rady Children's Institute for Genomic Medicine, Rady Children's Hospital, San Diego, CA, USA.
Bin GuanOphthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
Stacey HallProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Friedhelm HildebrandtDepartment of Pediatrics, Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Robert B HufnagelOphthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
Julie A JurgensProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Akanksha KhorgadeGenomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Gabrielle LemireCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Emily LiauCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Jialan MaProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Jill A MaddenThe 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.
Brian MangilogCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Brandy M McNultyDepartment of Biomolecular Engineering, University of California Santa Cruz, Santa Cruz, CA, USA.
Olfa MessaoudCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Shloka NegiUC Santa Cruz Genomics Institute, University of California Santa Cruz, Santa Cruz, CA, USA.ORCID 0000-0002-9839-4030
Emily O'HeirCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Melanie C O'LearyCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Ikeoluwa Osei-OwusuCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Katrin ÕunapGenetics and Personalized Medicine Clinic, Tartu University Hospital & Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
Lynn PaisCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Sander PajusaluGenetics and Personalized Medicine Clinic, Tartu University Hospital & Institute of Clinical Medicine, University of Tartu, Tartu, Estonia.
Alicia PhamProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Eric A PierceProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Emma Pierce-HoffmanCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Gianina RavenscroftCentre for Medical Research, University of Western Australia, Harry Perkins Institute of Medical Research, Perth, WA, Australia.
Tony RoscioliNeuroscience Research Australia (NeuRA), Sydney, NSW, Australia; New South Wales Health Pathology Randwick Genomics, Prince of Wales Hospital, Sydney, NSW, Australia.
Vijay G SankaranProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID 0000-0003-0044-443X
Jillian SerranoCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Elliott H SherrDepartment of Neurology, University of California, San Francisco, CA, USA.
Shirlee ShrilDepartment of Pediatrics, Division of Nephrology, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
Moriel Singer-BerkProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Hana SnowProgram in Medical and Population Genetics, Broad Institute of MIT and Harvard, Cambridge, MA, USA.
Volker StraubJohn Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK.ORCID 0000-0001-9046-3540
Derek TaiCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Tiong Y TanVictorian Clinical Genetics Services, Royal Children's Hospital, Melbourne, Victoria, Australia.ORCID 0000-0001-8455-7778
Ana TöpfJohn Walton Muscular Dystrophy Research Centre, Newcastle University and Newcastle Hospitals NHS Foundation Trust, Newcastle Upon Tyne, UK.
Ehsan UllahOphthalmic Genetics and Visual Function Branch, National Eye Institute, National Institutes of Health, Bethesda, MD, USA.
Grace VanNoyCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Ivo ViolichUC Santa Cruz Genomics Institute, University of California Santa Cruz, Santa Cruz, CA, USA.
Mark WalkerCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Susan M WhiteVictorian Clinical Genetics Services, Royal Children's Hospital, Melbourne, Victoria, Australia.
Monica H WojcikCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.ORCID 0000-0002-8162-5031
Emma MitchellGenomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Aziz M Al'KhafajiGenomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Sheila DodgeGenomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Kiran GarimellaData Sciences Platform, Broad Institute of MIT and Harvard, Cambridge, MA 02142, USA.ORCID 0000-0002-6212-5736
Niall J LennonBroad Clinical Labs (BCL), Broad Institute of MIT and Harvard, Cambridge, MA, USA.ORCID 0000-0002-2874-7371
Stacey B GabrielGenomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA, 02142, USA.
Karen H MigaUC Santa Cruz Genomics Institute, University of California Santa Cruz, Santa Cruz, CA, USA.
Benedict PatenUC Santa Cruz Genomics Institute, University of California Santa Cruz, Santa Cruz, CA, USA.
Heidi L RehmCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Anne O'Donnell-LuriaCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.ORCID 0000-0001-6418-9592
Harrison BrandCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.
Michael E TalkowskiCenter for Genomic Medicine, Massachusetts General Hospital, Boston, MA, USA.

Funding

Joint Center for Mendelian GenomicsUM1HG008900 · NHGRI · BROAD INSTITUTE, INC. · PI O'DONNELL-LURIA, ANNE, REHM, HEIDI L · 2016 to 2020
$16.5M
Precision Medicine for Inherited Retinal DegenerationsR01EY012910 · NEI · UNIVERSITY OF PENNSYLVANIA · PI Eric A Pierce · 1999 to 2026
$15.9M
University of Washington (UW) Mendelian Genomics Data Coordinating CenterU24HG011746 · NHGRI · UNIVERSITY OF WASHINGTON · PI Susanne May, ALI SHOJAIE · 2021 to 2026
$14.8M
Broad Institute Mendelian Genomic Research CenterU01HG011755 · NHGRI · BROAD INSTITUTE, INC. · PI Anne O'Donnell-Luria, MICHAEL E TALKOWSKI · 2021 to 2026
$14.6M
TRAINING GRANT IN GENETICST32GM007748 · NIGMS · HARVARD UNIVERSITY (MEDICAL SCHOOL) · PI Anne O'Donnell-Luria, Louise Wilkins-Haug · 1985 to 2026
$12.0M
Genetic Analysis and Manipulation Core (GAEC)P50HD105351 · NICHD · BOSTON CHILDREN'S HOSPITAL · PI Hisashi Umemori · 2021 to 2026
$9.4M
Clinical Diagnostic Sequencing of Structural VariationR01HD081256 · NICHD · MASSACHUSETTS GENERAL HOSPITAL · PI TALKOWSKI, MICHAEL E · 2015 to 2025
$7.2M
Supplement request for Training GrantT32NS007473 · NINDS · CHILDREN'S HOSPITAL BOSTON · PI Elizabeth C. Engle, Thomas L. Schwarz · 1999 to 2026
$6.9M
Systems Biology of Bone Marrow Failure and MDS for Precision MedicineRC2DK122533 · NIDDK · BOSTON CHILDREN'S HOSPITAL · PI FIGUEROA, MARIA EUGENIA, FLEMING, MARK D · 2019 to 2023
$6.4M
Scalable tool and comprehensive maps to interpret structural variation across the neuropsychiatric spectrumR01MH115957 · NIMH · BROAD INSTITUTE, INC. · PI TALKOWSKI, MICHAEL E · 2019 to 2025
$5.4M
Training Program in the Molecular Bases of Eye DiseasesT32EY007145 · NEI · SCHEPENS EYE RESEARCH INSTITUTE · PI Patricia Ann D'Amore, MEREDITH GREGORY-KSANDER · 1997 to 2026
$4.5M
Integration of polygenic risk and facial morphometrics to decipher the genetic susceptibility of orofacial cleftingR01DE031261 · NIDCR · MASSACHUSETTS GENERAL HOSPITAL · PI Harrison Brand · 2022 to 2026
$3.8M
NEI NIH HHS R01 EY012910NEI NIH HHS T32 EY007145NHGRI NIH HHS R01 HG009141NHGRI NIH HHS T32 HG010464NHGRI NIH HHS U01 HG011755NHGRI NIH HHS U24 HG011746NHGRI NIH HHS UM1 HG008900NIAMS NIH HHS K23 AR083505NICHD NIH HHS P50 HD105351NICHD NIH HHS R01 HD081256NICHD NIH HHS R01 HD105266NIDCR NIH HHS R00 DE026824NIDCR NIH HHS R01 DE030342NIDCR NIH HHS R01 DE031261NIDDK NIH HHS RC2 DK122533NIGMS NIH HHS T32 GM007748NIMH NIH HHS R01 MH115957NINDS NIH HHS T32 NS007473
6 · The paper itself

Abstract

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

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PMID42396270
PMCPMC13321193

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