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Steyaert, W.* ; Sagath, L.* ; Demidov, G.* ; Yépez, V.A.* ; Esteve-Codina, A.* ; Gagneur, J. ; Ellwanger, K.* ; Derks, R.* ; Weiss, M.C.* ; den Ouden, A.* ; van den Heuvel, S.* ; Swinkels, H.* ; Zomer, N.* ; Steehouwer, M.* ; O'Gorman, L.* ; Astuti, G.* ; Neveling, K.* ; Schüle, R.* ; Xu, J.* ; Synofzik, M.* ; Beijer, D.* ; Hengel, H.* ; Schöls, L.* ; Claeys, K.G.* ; Baets, J.* ; Van de Vondel, L.* ; Ferlini, A.* ; Selvatici, R.* ; Morsy, H.* ; Saeed Abd Elmaksoud, M.* ; Straub, V.* ; Müller, J.* ; Pini, V.* ; Perry, L.* ; Sarkozy, A.* ; Zaharieva, I.* ; Muntoni, F.* ; Bugiardini, E.* ; Polavarapu, K.* ; Horvath, R.* ; Reid, E.* ; Lochmüller, H.* ; Spinazzi, M.* ; Savarese, M.* ; Matalonga, L.* ; Laurie, S.* ; Brunner, H.G.* ; Graessner, H.* ; Beltran, S.* ; Ossowski, S.* ; Vissers, L.E.L.M.* ; Gilissen, C.* ; Hoischen, A.*

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

Genome Res. 35, 755-768 (2025)
Postprint DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
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 MCF2/FGF13 fusion and a PSMA3 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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Publication type Article: Journal article
Document type Scientific Article
Keywords Hereditary Spastic Paraplegia; Mutations; Spectrum; Protein; Repeat; Expansion; Platform; Variant
ISSN (print) / ISBN 1088-9051
e-ISSN 1549-5469
Journal Genome Research
Quellenangaben Volume: 35, Issue: 4, Pages: 755-768 Article Number: , Supplement: ,
Publisher Cold Spring Harbor Laboratory Press
Publishing Place 1 Bungtown Rd, Cold Spring Harbor, Ny 11724 Usa
Reviewing status Peer reviewed
Institute(s) Institute of Computational Biology (ICB)
Grants ZonMW (The Netherlands Organization for Health Research and Development) Vici grant
ERN on Rare Neurological Diseases (ERN RND)
Deutsche Forschungsgemeinschaft (DFG, German Research Foundation)
Sigrid Juselius Foundation
Bundesministerium fur Bildung und Forschung (BMBF)
National Institute of Neurological Disorders and Stroke (NINDS)
DFG
Canadian Institutes of Health Research (CIHR) for Foundation
Canada Foundation for Innovation
Canada Research Chairs program (Canada Research Chair in Neuromuscular Genomics and Health)
European Commission
Canada Research Coordinating Committee New Frontiers in Research Fund
Government of Canada's Canada First Research Excellence Fund (CFREF)
European Union