TY  - JOUR
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
Y1  - 2025/04/01 
JF  - Genome Research 
JO  - Genome Research 
SP  - 755 
EP  - 768 
DO  - 10.1101/gr.279414.124 
VL  - 35 
IS  - 4 
UR  - http://genome.cshlp.org/content/35/4/755.abstract 
N2  - 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. 
ER  -