@article{Steyaert01042025,
author = {Steyaert, Wouter and Sagath, Lydia and Demidov, German and Yépez, Vicente A. and Esteve-Codina, Anna and Gagneur, Julien and Ellwanger, Kornelia and Derks, Ronny and Weiss, Marjan and den Ouden, Amber and van den Heuvel, Simone and Swinkels, Hilde and Zomer, Nick and Steehouwer, Marloes and O'Gorman, Luke and Astuti, Galuh and Neveling, Kornelia and Schüle, Rebecca and Xu, Jishu and Synofzik, Matthis and Beijer, Danique and Hengel, Holger and Schöls, Ludger and Claeys, Kristl G. and Baets, Jonathan and Van de Vondel, Liedewei and Ferlini, Alessandra and Selvatici, Rita and Morsy, Heba and Saeed Abd Elmaksoud, Marwa and Straub, Volker and Müller, Juliane and Pini, Veronica and Perry, Luke and Sarkozy, Anna and Zaharieva, Irina and Muntoni, Francesco and Bugiardini, Enrico and Polavarapu, Kiran and Horvath, Rita and Reid, Evan and Lochmüller, Hanns and Spinazzi, Marco and Savarese, Marco and Solve-RD DITF-ITHACA, Solve-RD DITF-Euro-NMD, Solve-RD DITF-RND, Solve-RD DITF-EpiCARE and Matalonga, Leslie and Laurie, Steven and Brunner, Han G. and Graessner, Holm and Beltran, Sergi and Ossowski, Stephan and Vissers, Lisenka E.L.M. and Gilissen, Christian and Hoischen, Alexander and on behalf of the Solve-RD consortium}, 
title = {Unraveling undiagnosed rare disease cases by HiFi long-read genome sequencing},
volume = {35}, 
number = {4}, 
pages = {755-768}, 
year = {2025}, 
doi = {10.1101/gr.279414.124}, 
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 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.}, 
URL = {http://genome.cshlp.org/content/35/4/755.abstract}, 
eprint = {http://genome.cshlp.org/content/35/4/755.full.pdf+html}, 
journal = {Genome Research} 
}