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000277999 1001_ $$00000-0001-8393-0788$$aSteyaert, Wouter$$b0
000277999 245__ $$aUnraveling undiagnosed rare disease cases by HiFi long-read genome sequencing.
000277999 260__ $$aStanford, Calif.$$bHighWire Press$$c2025
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000277999 520__ $$aSolve-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.
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000277999 650_2 $$2MeSH$$aHumans
000277999 650_2 $$2MeSH$$aRare Diseases: genetics
000277999 650_2 $$2MeSH$$aRare Diseases: diagnosis
000277999 650_2 $$2MeSH$$aMale
000277999 650_2 $$2MeSH$$aFemale
000277999 650_2 $$2MeSH$$aWhole Genome Sequencing: methods
000277999 650_2 $$2MeSH$$aPolymorphism, Single Nucleotide
000277999 650_2 $$2MeSH$$aGenome, Human
000277999 650_2 $$2MeSH$$aPedigree
000277999 650_2 $$2MeSH$$aUndiagnosed Diseases: genetics
000277999 650_2 $$2MeSH$$aINDEL Mutation
000277999 7001_ $$00000-0002-6754-3830$$aSagath, Lydia$$b1
000277999 7001_ $$aDemidov, German$$b2
000277999 7001_ $$aYépez, Vicente A$$b3
000277999 7001_ $$aEsteve-Codina, Anna$$b4
000277999 7001_ $$00000-0002-8924-8365$$aGagneur, Julien$$b5
000277999 7001_ $$aEllwanger, Kornelia$$b6
000277999 7001_ $$aDerks, Ronny$$b7
000277999 7001_ $$aWeiss, Marjan$$b8
000277999 7001_ $$aden Ouden, Amber$$b9
000277999 7001_ $$avan den Heuvel, Simone$$b10
000277999 7001_ $$aSwinkels, Hilde$$b11
000277999 7001_ $$aZomer, Nick$$b12
000277999 7001_ $$aSteehouwer, Marloes$$b13
000277999 7001_ $$aO'Gorman, Luke$$b14
000277999 7001_ $$aAstuti, Galuh$$b15
000277999 7001_ $$aNeveling, Kornelia$$b16
000277999 7001_ $$0P:(DE-2719)2812018$$aSchüle-Freyer, Rebecca$$b17$$udzne
000277999 7001_ $$aXu, Jishu$$b18
000277999 7001_ $$0P:(DE-2719)2811275$$aSynofzik, Matthis$$b19
000277999 7001_ $$0P:(DE-2719)9002605$$aBeijer, Danique$$b20$$udzne
000277999 7001_ $$aHengel, Holger$$b21
000277999 7001_ $$0P:(DE-2719)2810795$$aSchöls, Ludger$$b22$$udzne
000277999 7001_ $$aClaeys, Kristl G$$b23
000277999 7001_ $$aBaets, Jonathan$$b24
000277999 7001_ $$aVan de Vondel, Liedewei$$b25
000277999 7001_ $$aFerlini, Alessandra$$b26
000277999 7001_ $$aSelvatici, Rita$$b27
000277999 7001_ $$aMorsy, Heba$$b28
000277999 7001_ $$aSaeed Abd Elmaksoud, Marwa$$b29
000277999 7001_ $$00000-0001-9046-3540$$aStraub, Volker$$b30
000277999 7001_ $$aMüller, Juliane$$b31
000277999 7001_ $$aPini, Veronica$$b32
000277999 7001_ $$aPerry, Luke$$b33
000277999 7001_ $$aSarkozy, Anna$$b34
000277999 7001_ $$aZaharieva, Irina$$b35
000277999 7001_ $$00000-0002-9102-5232$$aMuntoni, Francesco$$b36
000277999 7001_ $$00000-0002-9709-6699$$aBugiardini, Enrico$$b37
000277999 7001_ $$aPolavarapu, Kiran$$b38
000277999 7001_ $$aHorvath, Rita$$b39
000277999 7001_ $$aReid, Evan$$b40
000277999 7001_ $$aLochmüller, Hanns$$b41
000277999 7001_ $$00000-0003-0048-9558$$aSpinazzi, Marco$$b42
000277999 7001_ $$00000-0002-2591-244X$$aSavarese, Marco$$b43
000277999 7001_ $$aSolve-RD DITF-ITHACA, Solve-RD DITF-Euro-NMD, Solve-RD DITF-RND, Solve-RD DITF-EpiCARE$$b44$$eCollaboration Author
000277999 7001_ $$aMatalonga, Leslie$$b45
000277999 7001_ $$aLaurie, Steven$$b46
000277999 7001_ $$aBrunner, Han G$$b47
000277999 7001_ $$aGraessner, Holm$$b48
000277999 7001_ $$aBeltran, Sergi$$b49
000277999 7001_ $$00000-0002-7416-9568$$aOssowski, Stephan$$b50
000277999 7001_ $$00000-0001-6470-5497$$aVissers, Lisenka E L M$$b51
000277999 7001_ $$00000-0003-1693-9699$$aGilissen, Christian$$b52
000277999 7001_ $$aHoischen, Alexander$$b53
000277999 7001_ $$aconsortium, Solve-RD$$b54$$eCollaboration Author
000277999 773__ $$0PERI:(DE-600)1483456-X$$a10.1101/gr.279414.124$$gVol. 35, no. 4, p. 755 - 768$$n4$$p755 - 768$$tGenome research$$v35$$x1054-9803$$y2025
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