TY  - JOUR
AU  - Steyaert, Wouter
AU  - Sagath, Lydia
AU  - Demidov, German
AU  - Yépez, Vicente A
AU  - Esteve-Codina, Anna
AU  - Gagneur, Julien
AU  - Ellwanger, Kornelia
AU  - Derks, Ronny
AU  - Weiss, Marjan
AU  - den Ouden, Amber
AU  - van den Heuvel, Simone
AU  - Swinkels, Hilde
AU  - Zomer, Nick
AU  - Steehouwer, Marloes
AU  - O'Gorman, Luke
AU  - Astuti, Galuh
AU  - Neveling, Kornelia
AU  - Schüle-Freyer, Rebecca
AU  - Xu, Jishu
AU  - Synofzik, Matthis
AU  - Beijer, Danique
AU  - Hengel, Holger
AU  - Schöls, Ludger
AU  - Claeys, Kristl G
AU  - Baets, Jonathan
AU  - Van de Vondel, Liedewei
AU  - Ferlini, Alessandra
AU  - Selvatici, Rita
AU  - Morsy, Heba
AU  - Saeed Abd Elmaksoud, Marwa
AU  - Straub, Volker
AU  - Müller, Juliane
AU  - Pini, Veronica
AU  - Perry, Luke
AU  - Sarkozy, Anna
AU  - Zaharieva, Irina
AU  - Muntoni, Francesco
AU  - Bugiardini, Enrico
AU  - Polavarapu, Kiran
AU  - Horvath, Rita
AU  - Reid, Evan
AU  - Lochmüller, Hanns
AU  - Spinazzi, Marco
AU  - Savarese, Marco
AU  - Matalonga, Leslie
AU  - Laurie, Steven
AU  - Brunner, Han G
AU  - Graessner, Holm
AU  - Beltran, Sergi
AU  - Ossowski, Stephan
AU  - Vissers, Lisenka E L M
AU  - Gilissen, Christian
AU  - Hoischen, Alexander
TI  - Unraveling undiagnosed rare disease cases by HiFi long-read genome sequencing.
JO  - Genome research
VL  - 35
IS  - 4
SN  - 1054-9803
CY  - Stanford, Calif.
PB  - HighWire Press
M1  - DZNE-2025-00526
SP  - 755 - 768
PY  - 2025
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
KW  - Humans
KW  - Rare Diseases: genetics
KW  - Rare Diseases: diagnosis
KW  - Male
KW  - Female
KW  - Whole Genome Sequencing: methods
KW  - Polymorphism, Single Nucleotide
KW  - Genome, Human
KW  - Pedigree
KW  - Undiagnosed Diseases: genetics
KW  - INDEL Mutation
LB  - PUB:(DE-HGF)16
C2  - pmc:PMC12047270
C6  - pmid:40138663
DO  - DOI:10.1101/gr.279414.124
UR  - https://pub.dzne.de/record/277999
ER  -