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@ARTICLE{Steyaert:277999,
      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-Freyer, 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 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},
      collaboration = {Solve-RD DITF-ITHACA, Solve-RD DITF-Euro-NMD, Solve-RD
                      DITF-RND, Solve-RD DITF-EpiCARE and consortium, Solve-RD},
      title        = {{U}nraveling undiagnosed rare disease cases by {H}i{F}i
                      long-read genome sequencing.},
      journal      = {Genome research},
      volume       = {35},
      number       = {4},
      issn         = {1054-9803},
      address      = {Stanford, Calif.},
      publisher    = {HighWire Press},
      reportid     = {DZNE-2025-00526},
      pages        = {755 - 768},
      year         = {2025},
      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.},
      keywords     = {Humans / Rare Diseases: genetics / Rare Diseases: diagnosis
                      / Male / Female / Whole Genome Sequencing: methods /
                      Polymorphism, Single Nucleotide / Genome, Human / Pedigree /
                      Undiagnosed Diseases: genetics / INDEL Mutation},
      cin          = {AG Gasser / AG Schöls},
      ddc          = {540},
      cid          = {I:(DE-2719)1210000 / I:(DE-2719)5000005},
      pnm          = {353 - Clinical and Health Care Research (POF4-353)},
      pid          = {G:(DE-HGF)POF4-353},
      typ          = {PUB:(DE-HGF)16},
      pmc          = {pmc:PMC12047270},
      pubmed       = {pmid:40138663},
      doi          = {10.1101/gr.279414.124},
      url          = {https://pub.dzne.de/record/277999},
}