RT Journal
A1 Steyaert, Wouter
A1 Sagath, Lydia
A1 Demidov, German
A1 Yépez, Vicente A.
A1 Esteve-Codina, Anna
A1 Gagneur, Julien
A1 Ellwanger, Kornelia
A1 Derks, Ronny
A1 Weiss, Marjan
A1 den Ouden, Amber
A1 van den Heuvel, Simone
A1 Swinkels, Hilde
A1 Zomer, Nick
A1 Steehouwer, Marloes
A1 O'Gorman, Luke
A1 Astuti, Galuh
A1 Neveling, Kornelia
A1 Schüle, Rebecca
A1 Xu, Jishu
A1 Synofzik, Matthis
A1 Beijer, Danique
A1 Hengel, Holger
A1 Schöls, Ludger
A1 Claeys, Kristl G.
A1 Baets, Jonathan
A1 Van de Vondel, Liedewei
A1 Ferlini, Alessandra
A1 Selvatici, Rita
A1 Morsy, Heba
A1 Saeed Abd Elmaksoud, Marwa
A1 Straub, Volker
A1 Müller, Juliane
A1 Pini, Veronica
A1 Perry, Luke
A1 Sarkozy, Anna
A1 Zaharieva, Irina
A1 Muntoni, Francesco
A1 Bugiardini, Enrico
A1 Polavarapu, Kiran
A1 Horvath, Rita
A1 Reid, Evan
A1 Lochmüller, Hanns
A1 Spinazzi, Marco
A1 Savarese, Marco
A1 Solve-RD DITF-ITHACA, Solve-RD DITF-Euro-NMD, Solve-RD DITF-RND, Solve-RD DITF-EpiCARE
A1 Matalonga, Leslie
A1 Laurie, Steven
A1 Brunner, Han G.
A1 Graessner, Holm
A1 Beltran, Sergi
A1 Ossowski, Stephan
A1 Vissers, Lisenka E.L.M.
A1 Gilissen, Christian
A1 Hoischen, Alexander
A1 on behalf of the Solve-RD consortium
T1 Unraveling undiagnosed rare disease cases by HiFi long-read genome sequencing
JF Genome Research 
JO Genome Research 
YR 2025 
FD April 01 
VO 35 
IS 4 
SP 755 
OP 768 
DO 10.1101/gr.279414.124 
UL http://genome.cshlp.org/content/35/4/755.abstract 
AB 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.