Unraveling undiagnosed rare disease cases by HiFi long-read genome sequencing

Solve-RD is a pan-European rare disease (RD) research program that aims to identify disease-causing genetic variants in previously undiagnosed RD families. We utilized 10-fold coverage HiFi long-read sequencing (LRS) for detecting causative structural variants (SVs), single-nucleotide variants (SNVs), insertion-deletions (indels), and short tandem repeat (STR) expansions in previously studied RD families without a clear molecular diagnosis. Our cohort includes 293 individuals from 114 genetically undiagnosed RD families selected by European Reference Network (ERN) experts. Of these, 21 families were affected by so-called "unsolvable" syndromes for which genetic causes remain unknown and for which prior testing was not a prerequisite. The remaining 93 families had at least one individual affected by a rare neurological, neuromuscular, or epilepsy disorder without a genetic diagnosis despite extensive prior testing. Clinical interpretation and orthogonal validation of variants in known disease genes yielded 12 novel genetic diagnoses due to de novo and rare inherited SNVs, indels, SVs, and STR expansions. In an additional five families, we identified a candidate disease-causing variant, including an <i>MCF2</i>/<i>FGF13</i> fusion and a <i>PSMA3</i> deletion. However, no common genetic cause was identified in any of the "unsolvable" syndromes. Taken together, we found (likely) disease-causing genetic variants in 11.8% of previously unsolved families and additional candidate disease-causing SVs in another 5.4% of these families. In conclusion, our results demonstrate the potential added value of HiFi long-read genome sequencing in undiagnosed rare diseases.

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Journal
Genome Research
Published
2025-03-26
DOI
https://doi.org/10.1101/gr.279414.124
Citations
18
Primary Topic
Genomics and Rare Diseases
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article

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article

Unraveling undiagnosed rare disease cases by HiFi long-read genome sequencing

Julien Gagneur, Heba Morsy, Kornelia Neveling, Rita Selvatici et al.
18 citations
Genome Research
Genomics and Rare Diseases
article

Unraveling undiagnosed rare disease cases by HiFi long-read genome sequencing

Julien Gagneur, Heba Morsy, Kornelia Neveling, Rita Selvatici, German Demidov, Anna Esteve‐Codina, Marco Spinazzi, Amber den Ouden, Volker Straub, Christian Gilissen, Han G. Brunner, Alexander Hoischen, Matthis Synofzik, Marjan M. Weiss, Kristl G. Claeys, Rita Horváth, Lisenka E.L.M. Vissers, Veronica Pini, Alessandra Ferlini, Holger Hengel, Evan Reid, Ronny Derks, Leslie Matalonga, Anna Sárközy, Galuh Astuti, Kiran Polavarapu, Hanns Lochmüller, Hilde Swinkels, Sergi Beltrán, Kornelia Ellwanger, Wouter Steyaert, Irina Zaharieva, Luke Perry, Liedewei Van de Vondel, Lydia Sagath, Danique Beijer, Ludger J. Schöls, Luke O’Gorman, Simone van den Heuvel, Jonathan Baets, Holm Graeßner, Marco Savarese, Steven Laurie, Enrico Bugiardini, Vicente A. Yépez, Stephan Ossowski, Rebecca Schüle, Francesco Muntoni, Nick Zomer, Juliane Müller, Jishu Xu, Marloes Steehouwer, Marwa Saeed Abd Elmaksoud
article en
18 citations

Abstract

Solve-RD is a pan-European rare disease (RD) research program that aims to identify disease-causing genetic variants in previously undiagnosed RD families. We utilized 10-fold coverage HiFi long-read sequencing (LRS) for detecting causative structural variants (SVs), single-nucleotide variants (SNVs), insertion-deletions (indels), and short tandem repeat (STR) expansions in previously studied RD families without a clear molecular diagnosis. Our cohort includes 293 individuals from 114 genetically undiagnosed RD families selected by European Reference Network (ERN) experts. Of these, 21 families were affected by so-called "unsolvable" syndromes for which genetic causes remain unknown and for which prior testing was not a prerequisite. The remaining 93 families had at least one individual affected by a rare neurological, neuromuscular, or epilepsy disorder without a genetic diagnosis despite extensive prior testing. Clinical interpretation and orthogonal validation of variants in known disease genes yielded 12 novel genetic diagnoses due to de novo and rare inherited SNVs, indels, SVs, and STR expansions. In an additional five families, we identified a candidate disease-causing variant, including an <i>MCF2</i>/<i>FGF13</i> fusion and a <i>PSMA3</i> deletion. However, no common genetic cause was identified in any of the "unsolvable" syndromes. Taken together, we found (likely) disease-causing genetic variants in 11.8% of previously unsolved families and additional candidate disease-causing SVs in another 5.4% of these families. In conclusion, our results demonstrate the potential added value of HiFi long-read genome sequencing in undiagnosed rare diseases.

Genome ResearchVol. 35(4)
Allen Institute for Brain Science (US), University of Helsinki (FI), Radboud University Nijmegen (NL), University of Antwerp (BE), University of Ottawa (CA), University of Ferrara (IT), Heidelberg University (DE), University of Cambridge (GB), Children's Hospital of Eastern Ontario (CA), Great Ormond Street Hospital (GB), Maastricht University Medical Centre (NL), Ottawa Hospital (CA), German Center for Neurodegenerative Diseases (DE), Newcastle upon Tyne Hospitals NHS Foundation Trust (GB), University Hospital Heidelberg (DE), University Medical Center (US), Radboud University Medical Center (NL), Helmholtz Zentrum München (DE), Maastricht University (NL), Universitätsklinikum Tübingen (DE), MIND Research Institute (US), Antwerp University Hospital (BE), Finland University (FI), Radboud Institute for Molecular Life Sciences (NL), Centre Hospitalier Universitaire d'Angers (FR), Institute of Human Genetics (PL), University Children's Hospital Tübingen (DE), Institute for Medical Research (MY), NIHR Newcastle Biomedical Research Centre (GB), Hertie Institute for Clinical Brain Research (DE), Centro Nacional de Análisis Genómico (ES), National Hospital for Neurology and Neurosurgery (GB), VIB-KU Leuven Center for Brain & Disease Research (BE), Folkhälsans Forskningscentrum (FI), NIHR Great Ormond Street Hospital Biomedical Research Centre (GB), University College London (GB), Technical University of Munich (DE), Universitat de Barcelona (ES), University of Tübingen (DE), Alexandria University (EG), Newcastle University (GB), KU Leuven (BE)
Government of Canada, European Commission, Deutsche Forschungsgemeinschaft, Canada Research Chairs, Canada Foundation for Innovation, ZonMw, Bundesministerium für Bildung und Forschung, Sigrid Juséliuksen Säätiö, Canada First Research Excellence Fund, Canadian Institutes of Health Research, National Institute of Neurological Disorders and Stroke
Good health and well-being
Genomics and Rare Diseases
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