Next-generation phenotyping integrated in a national framework for patients with ultrarare disorders improves genetic diagnostics and yields new molecular findings.

التفاصيل البيبلوغرافية
العنوان:	Next-generation phenotyping integrated in a national framework for patients with ultrarare disorders improves genetic diagnostics and yields new molecular findings.
المؤلفون:	Schmidt A; Institute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Danyel M; Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany.; BIH Charité Clinician Scientist Program, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany., Grundmann K; Institute for Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany., Brunet T; Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, München, Germany., Klinkhammer H; Institute for Genomic Statistics and Bioinformatics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.; Institut für Medizinische Biometrie, Informatik und Epidemiologie, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Hsieh TC; Institute for Genomic Statistics and Bioinformatics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Engels H; Institute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Peters S; Institute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Knaus A; Institute for Genomic Statistics and Bioinformatics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Moosa S; Institute for Medical Genetics, Stellenbosch University, Cape Town, South Africa., Averdunk L; Department of Pediatrics, University Hospital Düsseldorf, Düsseldorf, Germany., Boschann F; Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany.; BIH Charité Clinician Scientist Program, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany., Sczakiel HL; Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany.; BIH Charité Clinician Scientist Program, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany., Schwartzmann S; Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany., Mensah MA; Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany.; BIH Charité Clinician Scientist Program, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany., Pantel JT; Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany.; Institute for Human Genetics and Genomic Medicine, Medical Faculty, Uniklinik RWTH Aachen University, Aachen, Germany., Holtgrewe M; Core Uni Bioinformatics, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany., Bösch A; Department of Pediatrics, Charité - Universitätsmedizin Berlin, Berlin, Germany., Weiß C; Department of Pediatrics, Charité - Universitätsmedizin Berlin, Berlin, Germany., Weinhold N; Department of Pediatrics, Charité - Universitätsmedizin Berlin, Berlin, Germany., Suter AA; Department of Pediatrics, Charité - Universitätsmedizin Berlin, Berlin, Germany., Stoltenburg C; Department of Pediatrics, Charité - Universitätsmedizin Berlin, Berlin, Germany., Neugebauer J; Department of Pediatrics, Charité - Universitätsmedizin Berlin, Berlin, Germany., Kallinich T; Department of Pediatrics, Charité - Universitätsmedizin Berlin, Berlin, Germany., Kaindl AM; Department of Pediatric Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany.; Center for Chronically Sick Children, Charité - Universitätsmedizin Berlin, Berlin, Germany.; Institute of Cell and Neurobiology, Charité - Universitätsmedizin Berlin, Berlin, Germany., Holzhauer S; Department of Pediatrics, Charité - Universitätsmedizin Berlin, Berlin, Germany., Bührer C; Department of Pediatrics, Charité - Universitätsmedizin Berlin, Berlin, Germany., Bufler P; Department of Pediatrics, Charité - Universitätsmedizin Berlin, Berlin, Germany., Kornak U; Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany., Ott CE; Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany., Schülke M; Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany., Nguyen HHP; Department of Human Genetics, Ruhr University Bochum, Bochum, Germany., Hoffjan S; Department of Human Genetics, Ruhr University Bochum, Bochum, Germany., Grasemann C; Department of Pediatrics Bochum and CeSER, Ruhr University Bochum, Bochum, Germany., Rothoeft T; Department of Pediatrics Bochum and CeSER, Ruhr University Bochum, Bochum, Germany., Brinkmann F; Department of Pediatrics Bochum and CeSER, Ruhr University Bochum, Bochum, Germany., Matar N; Department of Pediatrics Bochum and CeSER, Ruhr University Bochum, Bochum, Germany., Sivalingam S; Institute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Perne C; Institute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Mangold E; Institute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Kreiss M; Institute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Cremer K; Institute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Betz RC; Institute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Mücke M; Center for Rare Diseases, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Grigull L; Center for Rare Diseases, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Klockgether T; Department of Neurology, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Spier I; Institute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Heimbach A; Institute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Bender T; Center for Rare Diseases, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Brand F; Institute for Genomic Statistics and Bioinformatics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Stieber C; Center for Rare Diseases, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Morawiec AM; Center for Rare Diseases, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Karakostas P; Clinic for Internal Medicine III, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Schäfer VS; Clinic for Internal Medicine III, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Bernsen S; Center for Rare Diseases, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Weydt P; Department of Neurology, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Castro-Gomez S; Department of Neurology, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Aziz A; Department of Neurology, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Grobe-Einsler M; Department of Neurology, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Kimmich O; Department of Neurology, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Kobeleva X; Department of Neurology, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Önder D; Department of Neurology, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Lesmann H; Institute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Kumar S; Institute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Tacik P; Department of Neurology, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Basin MA; Institute for Genomic Statistics and Bioinformatics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Incardona P; Institute for Genomic Statistics and Bioinformatics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Lee-Kirsch MA; University Center for Rare Diseases, University Hospital Carl Gustav Carus, Dresden, Germany.; Department of Pediatrics, University Hospital Carl Gustav Carus, Dresden, Germany., Berner R; University Center for Rare Diseases, University Hospital Carl Gustav Carus, Dresden, Germany.; Department of Pediatrics, University Hospital Carl Gustav Carus, Dresden, Germany., Schuetz C; University Center for Rare Diseases, University Hospital Carl Gustav Carus, Dresden, Germany.; Department of Pediatrics, University Hospital Carl Gustav Carus, Dresden, Germany., Körholz J; University Center for Rare Diseases, University Hospital Carl Gustav Carus, Dresden, Germany.; Department of Pediatrics, University Hospital Carl Gustav Carus, Dresden, Germany., Kretschmer T; University Center for Rare Diseases, University Hospital Carl Gustav Carus, Dresden, Germany.; Department of Pediatrics, University Hospital Carl Gustav Carus, Dresden, Germany., Di Donato N; University Center for Rare Diseases, University Hospital Carl Gustav Carus, Dresden, Germany.; Institute for Clinical Genetics, University Hospital Carl Gustav Carus, Dresden, Germany., Schröck E; University Center for Rare Diseases, University Hospital Carl Gustav Carus, Dresden, Germany.; Institute for Clinical Genetics, University Hospital Carl Gustav Carus, Dresden, Germany., Heinen A; University Center for Rare Diseases, University Hospital Carl Gustav Carus, Dresden, Germany.; Department of Pediatrics, University Hospital Carl Gustav Carus, Dresden, Germany., Reuner U; University Center for Rare Diseases, University Hospital Carl Gustav Carus, Dresden, Germany.; Department of Neurology, University Hospital Carl Gustav Carus, Dresden, Germany., Hanßke AM; University Center for Rare Diseases, University Hospital Carl Gustav Carus, Dresden, Germany., Kaiser FJ; Institute of Human Genetics, University Hospital Essen, Essen, Germany., Manka E; Department of Pediatrics II, University Hospital Essen, Essen, Germany., Munteanu M; Institute of Human Genetics, University Hospital Essen, Essen, Germany., Kuechler A; Institute of Human Genetics, University Hospital Essen, Essen, Germany., Cordula K; Department of Pediatrics II, University Hospital Essen, Essen, Germany., Hirtz R; Department of Pediatrics II, University Hospital Essen, Essen, Germany., Schlapakow E; Department of Neurology, University Hospital Halle, Halle, Germany., Schlein C; Institute of Human Genetics, University Hospital Hamburg-Eppendorf, Hamburg, Germany., Lisfeld J; Institute of Human Genetics, University Hospital Hamburg-Eppendorf, Hamburg, Germany., Kubisch C; Institute of Human Genetics, University Hospital Hamburg-Eppendorf, Hamburg, Germany.; Martin Zeitz Center for Rare Diseases, University Hospital Hamburg-Eppendorf, Hamburg, Germany., Herget T; Institute of Human Genetics, University Hospital Hamburg-Eppendorf, Hamburg, Germany., Hempel M; Institute of Human Genetics, University Hospital Hamburg-Eppendorf, Hamburg, Germany.; Martin Zeitz Center for Rare Diseases, University Hospital Hamburg-Eppendorf, Hamburg, Germany.; Institute of Human Genetics, Heidelberg University, Heidelberg, Germany., Weiler-Normann C; Martin Zeitz Center for Rare Diseases, University Hospital Hamburg-Eppendorf, Hamburg, Germany.; I. Department of Medicine, University Hospital Hamburg-Eppendorf, Hamburg, Germany., Ullrich K; Martin Zeitz Center for Rare Diseases, University Hospital Hamburg-Eppendorf, Hamburg, Germany., Schramm C; Martin Zeitz Center for Rare Diseases, University Hospital Hamburg-Eppendorf, Hamburg, Germany.; I. Department of Medicine, University Hospital Hamburg-Eppendorf, Hamburg, Germany., Rudolph C; Martin Zeitz Center for Rare Diseases, University Hospital Hamburg-Eppendorf, Hamburg, Germany., Rillig F; Martin Zeitz Center for Rare Diseases, University Hospital Hamburg-Eppendorf, Hamburg, Germany., Groffmann M; Martin Zeitz Center for Rare Diseases, University Hospital Hamburg-Eppendorf, Hamburg, Germany., Muntau A; Department of Pediatrics, University Hospital Hamburg-Eppendorf, Hamburg, Germany., Tibelius A; Institute of Human Genetics, Heidelberg University, Heidelberg, Germany., Schwaibold EMC; Institute of Human Genetics, Heidelberg University, Heidelberg, Germany., Schaaf CP; Institute of Human Genetics, Heidelberg University, Heidelberg, Germany., Zawada M; Institute of Human Genetics, Heidelberg University, Heidelberg, Germany., Kaufmann L; Institute of Human Genetics, Heidelberg University, Heidelberg, Germany., Hinderhofer K; Institute of Human Genetics, Heidelberg University, Heidelberg, Germany., Okun PM; Center for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany., Kotzaeridou U; Center for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany., Hoffmann GF; Center for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany., Choukair D; Center for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany., Bettendorf M; Center for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany., Spielmann M; Institute of Human Genetics, University Hospital Schleswig-Holstein, Lübeck, Germany., Ripke A; Center for Rare Diseases, University Hospital Schleswig-Holstein, Lübeck, Germany., Pauly M; Department of Neurology, University Hospital Schleswig-Holstein, Lübeck, Germany.; Institute for Neurogenetics, University Hospital Schleswig-Holstein, Lübeck, Germany., Münchau A; Center for Rare Diseases, University Hospital Schleswig-Holstein, Lübeck, Germany.; Institute of Systems Motor Science, University of Lübeck, Lübeck, Germany., Lohmann K; Institute of Neurogenetics, University of Lübeck, Lübeck, Germany., Hüning I; Institute of Human Genetics, University Hospital Schleswig-Holstein, Lübeck, Germany., Hanker B; Institute of Human Genetics, University of Lübeck, Lübeck, Germany., Bäumer T; Center for Rare Diseases, University Hospital Schleswig-Holstein, Lübeck, Germany.; Institute of Systems Motor Science, University of Lübeck, Lübeck, Germany., Herzog R; Center for Rare Diseases, University Hospital Schleswig-Holstein, Lübeck, Germany.; Department of Neurology, University Hospital Schleswig-Holstein, Lübeck, Germany., Hellenbroich Y; Department of Human Genetics, University Hospital Schleswig-Holstein, Lübeck, Germany., Westphal DS; Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, München, Germany., Strom T; Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, München, Germany., Kovacs R; Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, München, Germany., Riedhammer KM; Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, München, Germany.; Department of Nephrology, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, München, Germany., Mayerhanser K; Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, München, Germany., Graf E; Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, München, Germany., Brugger M; Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, München, Germany., Hoefele J; Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, München, Germany., Oexle K; Institute of Neurogenomics, Helmholtz Zentrum München, München, Germany., Mirza-Schreiber N; Institute of Neurogenomics, Helmholtz Zentrum München, München, Germany., Berutti R; Institute of Neurogenomics, Helmholtz Zentrum München, München, Germany., Schatz U; Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, München, Germany., Krenn M; Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, München, Germany.; Department of Neurology, Medical University of Vienna, Wien, Austria., Makowski C; Department of Paediatrics, Adolescent Medicine and Neonatology, München, Germany., Weigand H; Dr. von Hauner Children's Hospital, University Hospital Munich, München, Germany., Schröder S; Dr. von Hauner Children's Hospital, University Hospital Munich, München, Germany., Rohlfs M; Dr. von Hauner Children's Hospital, University Hospital Munich, München, Germany., Vill K; Dr. von Hauner Children's Hospital, University Hospital Munich, München, Germany., Hauck F; Dr. von Hauner Children's Hospital, University Hospital Munich, München, Germany., Borggraefe I; Dr. von Hauner Children's Hospital, University Hospital Munich, München, Germany., Müller-Felber W; Dr. von Hauner Children's Hospital, University Hospital Munich, München, Germany., Kurth I; Institute for Human Genetics and Genomic Medicine, Medical Faculty, Uniklinik RWTH Aachen University, Aachen, Germany., Elbracht M; Institute for Human Genetics and Genomic Medicine, Medical Faculty, Uniklinik RWTH Aachen University, Aachen, Germany., Knopp C; Institute for Human Genetics and Genomic Medicine, Medical Faculty, Uniklinik RWTH Aachen University, Aachen, Germany., Begemann M; Institute for Human Genetics and Genomic Medicine, Medical Faculty, Uniklinik RWTH Aachen University, Aachen, Germany., Kraft F; Institute for Human Genetics and Genomic Medicine, Medical Faculty, Uniklinik RWTH Aachen University, Aachen, Germany., Lemke JR; Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.; Center for Rare Diseases, University of Leipzig Medical Center, Leipzig, Germany., Hentschel J; Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany., Platzer K; Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany., Strehlow V; Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany., Abou Jamra R; Institute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany., Kehrer M; Institute for Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany., Demidov G; Institute for Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany., Beck-Wödl S; Institute for Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany., Graessner H; Center for Rare Diseases, University of Tübingen, Tübingen, Germany., Sturm M; Institute for Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany., Zeltner L; Center for Rare Diseases, University of Tübingen, Tübingen, Germany., Schöls LJ; Department of Neurology, University of Tübingen, Tübingen, Germany., Magg J; Center for Rare Diseases, University of Tübingen, Tübingen, Germany., Bevot A; Department of Pediatric Neurology and Developmental Medicine, University of Tübingen, Tübingen, Germany., Kehrer C; Department of Pediatric Neurology and Developmental Medicine, University of Tübingen, Tübingen, Germany., Kaiser N; Department of Pediatric Neurology and Developmental Medicine, University of Tübingen, Tübingen, Germany., Turro E; Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA., Horn D; Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany., Grüters-Kieslich A; Berlin Centre for Rare Diseases, Charité - Universitätsmedizin Berlin, Berlin, Germany., Klein C; Dr. von Hauner Children's Hospital, University Hospital Munich, München, Germany., Mundlos S; Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany., Nöthen M; Institute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany., Riess O; Institute for Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany., Meitinger T; Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, München, Germany., Krude H; Berlin Centre for Rare Diseases, Charité - Universitätsmedizin Berlin, Berlin, Germany., Krawitz PM; Institute for Genomic Statistics and Bioinformatics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany. pkrawitz@uni-bonn.de., Haack T; Institute for Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany., Ehmke N; Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany.; BIH Charité Clinician Scientist Program, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany., Wagner M; Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, München, Germany.; Institute of Neurogenomics, Helmholtz Zentrum München, München, Germany.; Dr. von Hauner Children's Hospital, University Hospital Munich, München, Germany.
المصدر:	Nature genetics [Nat Genet] 2024 Jul 22. Date of Electronic Publication: 2024 Jul 22.
Publication Model:	Ahead of Print
نوع المنشور:	Journal Article
اللغة:	English
بيانات الدورية:	Publisher: Nature Pub. Co Country of Publication: United States NLM ID: 9216904 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1546-1718 (Electronic) Linking ISSN: 10614036 NLM ISO Abbreviation: Nat Genet Subsets: MEDLINE
أسماء مطبوعة:	Original Publication: New York, NY : Nature Pub. Co., c1992-
مستخلص:	Individuals with ultrarare disorders pose a structural challenge for healthcare systems since expert clinical knowledge is required to establish diagnoses. In TRANSLATE NAMSE, a 3-year prospective study, we evaluated a novel diagnostic concept based on multidisciplinary expertise in Germany. Here we present the systematic investigation of the phenotypic and molecular genetic data of 1,577 patients who had undergone exome sequencing and were partially analyzed with next-generation phenotyping approaches. Molecular genetic diagnoses were established in 32% of the patients totaling 370 distinct molecular genetic causes, most with prevalence below 1:50,000. During the diagnostic process, 34 novel and 23 candidate genotype-phenotype associations were identified, mainly in individuals with neurodevelopmental disorders. Sequencing data of the subcohort that consented to computer-assisted analysis of their facial images with GestaltMatcher could be prioritized more efficiently compared with approaches based solely on clinical features and molecular scores. Our study demonstrates the synergy of using next-generation sequencing and phenotyping for diagnosing ultrarare diseases in routine healthcare and discovering novel etiologies by multidisciplinary teams. (© 2024. The Author(s).)
References:	Nguengang Wakap, S. et al. Estimating cumulative point prevalence of rare diseases: analysis of the Orphanet database. Eur. J. Hum. Genet. 28, 165–173 (2020). (PMID: 3152785810.1038/s41431-019-0508-0) Blöß, S. et al. Diagnostic needs for rare diseases and shared prediagnostic phenomena: results of a German-wide expert Delphi survey. PLoS ONE 12, e0172532 (2017). (PMID: 28234950532530110.1371/journal.pone.0172532) Boycott, K. M. et al. International cooperation to enable the diagnosis of all rare genetic diseases. Am. J. Hum. Genet. 100, 695–705 (2017). (PMID: 28475856542035110.1016/j.ajhg.2017.04.003) Austin, C. P. et al. Future of rare diseases eesearch 2017–2027: an IRDiRC Perspective. Clin. Transl. Sci. 11, 21–27 (2018). (PMID: 2879644510.1111/cts.12500) Hochstenbach, R. et al. Array analysis and karyotyping: workflow consequences based on a retrospective study of 36,325 patients with idiopathic developmental delay in the Netherlands. Eur. J. Med. Genet. 52, 161–169 (2009). (PMID: 1936217410.1016/j.ejmg.2009.03.015) Choi, H. S. et al. Molecular diagnosis of hereditary spherocytosis by multi-gene target sequencing in Korea: matching with osmotic fragility test and presence of spherocyte. Orphanet J. Rare Dis. 14, 114 (2019). (PMID: 31122244653365210.1186/s13023-019-1070-0) Kochinke, K. et al. Systematic phenomics analysis deconvolutes genes mutated in intellectual disability into biologically coherent modules. Am. J. Hum. Genet. 98, 149–164 (2016). (PMID: 26748517471670510.1016/j.ajhg.2015.11.024) 100,000 Genomes Project Pilot Investigatorset al. 100,000 Genomes pilot on rare-disease diagnosis in health care—preliminary report. N. Engl. J. Med. 385, 1868–1880 (2021). (PMID: 10.1056/NEJMoa2035790) Rillig, F., Grüters, A., Schramm, C. & Krude, H. The interdisciplinary diagnosis of rare diseases: results of the TRANSLATE-NAMSE project. Dtsch. Arztebl. Int. 119, 469–475 (2022). (PMID: 356354379664985) Cao, Y. et al. A clinical survey of mosaic single nucleotide variants in disease-causing genes detected by exome sequencing. Genome Med. 11, 48 (2019). (PMID: 31349857666070010.1186/s13073-019-0658-2) Gambin, T. et al. Low-level parental somatic mosaic SNVs in exomes from a large cohort of trios with diverse suspected Mendelian conditions. Genet. Med. 22, 1768–1776 (2020). (PMID: 32655138760656310.1038/s41436-020-0897-z) Wright, C. F. et al. Clinically-relevant postzygotic mosaicism in parents and children with developmental disorders in trio exome sequencing data. Nat. Commun. 10, 2985 (2019). (PMID: 31278258661186310.1038/s41467-019-11059-2) Landrum, M. J. et al. ClinVar: improvements to accessing data. Nucleic Acids Res. 48, D835–D844 (2020). (PMID: 3177794310.1093/nar/gkz972) Martin, H. C. et al. Quantifying the contribution of recessive coding variation to developmental disorders. Science 362, 1161–1164 (2018). (PMID: 30409806672647010.1126/science.aar6731) Fridman, H. et al. The landscape of autosomal-recessive pathogenic variants in European populations reveals phenotype-specific effects. Am. J. Hum. Genet. 108, 608–619 (2021). (PMID: 33740458805933510.1016/j.ajhg.2021.03.004) Hu, H. et al. Genetics of intellectual disability in consanguineous families. Mol. Psychiatry 24, 1027–1039 (2019). (PMID: 2930207410.1038/s41380-017-0012-2) La Rocca, L. A. et al. Understanding recessive disease risk in multi-ethnic populations with different degrees of consanguinity. Am. J. Med. Genet. A 194, e63452 (2024). (PMID: 3792156310.1002/ajmg.a.63452) Posey, J. E. et al. Resolution of disease phenotypes resulting from multilocus genomic variation. N. Engl. J. Med. 376, 21–31 (2017). (PMID: 2795969710.1056/NEJMoa1516767) Mitani, T. et al. High prevalence of multilocus pathogenic variation in neurodevelopmental disorders in the Turkish population. Am. J. Hum. Genet. 108, 1981–2005 (2021). (PMID: 34582790854604010.1016/j.ajhg.2021.08.009) Turro, E. et al. Whole-genome sequencing of patients with rare diseases in a national health system. Nature 583, 96–102 (2020). (PMID: 32581362761055310.1038/s41586-020-2434-2) Körholz, J. et al. Novel mutation and expanding phenotype in IRF2BP2 deficiency. Rheumatology 62, 1699–1705 (2023). (PMID: 3619398810.1093/rheumatology/keac575) Mochel, F. et al. Variants in the SK2 channel gene (KCNN2) lead to dominant neurodevelopmental movement disorders. Brain 143, 3564–3573 (2020). (PMID: 3324288110.1093/brain/awaa346) Magg, T. et al. Heterozygous OAS1 gain-of-function variants cause an autoinflammatory immunodeficiency. Sci. Immunol. 6, eabf9564 (2021). (PMID: 34145065839250810.1126/sciimmunol.abf9564) den Hoed, J. et al. Mutation-specific pathophysiological mechanisms define different neurodevelopmental disorders associated with SATB1 dysfunction. Am. J. Hum. Genet. 108, 346–356 (2021). (PMID: 10.1016/j.ajhg.2021.01.007) Li, D. et al. Pathogenic variants in SMARCA5, a chromatin remodeler, cause a range of syndromic neurodevelopmental features. Sci. Adv. 7, eabf2066 (2021). (PMID: 33980485811591510.1126/sciadv.abf2066) Thaventhiran, J. E. D. et al. Whole-genome sequencing of a sporadic primary immunodeficiency cohort. Nature 583, 90–95 (2020). (PMID: 32499645733404710.1038/s41586-020-2265-1) Vogt, G. et al. Biallelic truncating variants in ATP9A cause a novel neurodevelopmental disorder involving postnatal microcephaly and failure to thrive. J. Med. Genet. 59, 662–668 (2022). (PMID: 3437905710.1136/jmedgenet-2021-107843) Stenton, S. L. et al. Impaired complex I repair causes recessive Leber’s hereditary optic neuropathy. J. Clin. Invest. 131, e138267 (2021). (PMID: 33465056795460010.1172/JCI138267) Horn, D. et al. Biallelic truncating variants in MAPKAPK5 cause a new developmental disorder involving neurological, cardiac, and facial anomalies combined with synpolydactyly. Genet. Med. 23, 679–688 (2021). (PMID: 3344202610.1038/s41436-020-01052-2) Brugger, M. et al. A homozygous truncating variant in CCDC186 in an individual with epileptic encephalopathy. Ann. Clin. Transl. Neurol. 8, 278–283 (2021). (PMID: 3325914610.1002/acn3.51260) Marafi, D. et al. A reverse genetics and genomics approach to gene paralog function and disease: Myokymia and the juxtaparanode. Am. J. Hum. Genet. 109, 1713–1723 (2022). (PMID: 35948005950207010.1016/j.ajhg.2022.07.006) Ebstein, F. et al. PSMC3 proteasome subunit variants are associated with neurodevelopmental delay and type I interferon production. Sci. Transl. Med. 15, eabo3189 (2023). (PMID: 372569371050636710.1126/scitranslmed.abo3189) Richard, E. M. et al. Bi-allelic variants in SPATA5L1 lead to intellectual disability, spastic-dystonic cerebral palsy, epilepsy, and hearing loss. Am. J. Hum. Genet. 108, 2006–2016 (2021). (PMID: 34626583854623310.1016/j.ajhg.2021.08.003) Liu, Z. et al. Hemizygous variants in protein phosphatase 1 regulatory subunit 3F (PPP1R3F) are associated with a neurodevelopmental disorder characterized by developmental delay, intellectual disability and autistic features. Hum. Mol. Genet. 32, 2981–2995 (2023). (PMID: 3753123710.1093/hmg/ddad124) Aref-Eshghi, E. et al. Genomic DNA methylation signatures enable concurrent diagnosis and clinical genetic variant classification in neurodevelopmental syndromes. Am. J. Hum. Genet. 102, 156–174 (2018). (PMID: 29304373577798310.1016/j.ajhg.2017.12.008) Mirza-Schreiber, N. et al. Blood DNA methylation provides an accurate biomarker of KMT2B-related dystonia and predicts onset. Brain 145, 644–654 (2022). (PMID: 3459068510.1093/brain/awab360) Cummings, B. B. et al. Improving genetic diagnosis in Mendelian disease with transcriptome sequencing. Sci. Transl. Med. 9, eaal5209 (2017). (PMID: 28424332554842110.1126/scitranslmed.aal5209) Murdock, D. R. et al. Transcriptome-directed analysis for Mendelian disease diagnosis overcomes limitations of conventional genomic testing. J. Clin. Invest. 131, e141500 (2021). (PMID: 33001864777338610.1172/JCI141500) Frésard, L. et al. Identification of rare-disease genes using blood transcriptome sequencing and large control cohorts. Nat. Med. 25, 911–919 (2019). (PMID: 31160820663430210.1038/s41591-019-0457-8) Hsieh, T.-C. et al. GestaltMatcher facilitates rare disease matching using facial phenotype descriptors. Nat. Genet. 54, 349–357 (2022). (PMID: 35145301927235610.1038/s41588-021-01010-x) Hsieh, T.-C. et al. PEDIA: prioritization of exome data by image analysis. Genet. Med. 21, 2807–2814 (2019). (PMID: 31164752689273910.1038/s41436-019-0566-2) Kircher, M. et al. A general framework for estimating the relative pathogenicity of human genetic variants. Nat. Genet. 46, 310–315 (2014). (PMID: 24487276399297510.1038/ng.2892) Robinson, P. N. et al. Improved exome prioritization of disease genes through cross-species phenotype comparison. Genome Res. 24, 340–348 (2014). (PMID: 24162188391242410.1101/gr.160325.113) Li, Q., Zhao, K., Bustamante, C. D., Ma, X. & Wong, W. H. Xrare: a machine learning method jointly modeling phenotypes and genetic evidence for rare disease diagnosis. Genet. Med. 21, 2126–2134 (2019). (PMID: 30675030675231810.1038/s41436-019-0439-8) Robinson, P. N. et al. Interpretable clinical genomics with a likelihood ratio paradigm. Am. J. Hum. Genet. 107, 403–417 (2020). (PMID: 32755546747701710.1016/j.ajhg.2020.06.021) Birgmeier, J. et al. AMELIE speeds Mendelian diagnosis by matching patient phenotype and genotype to primary literature. Sci. Transl. Med. 12, eaau9113 (2020). (PMID: 32434849936692810.1126/scitranslmed.aau9113) Brand, F. et al. Next-generation phenotyping contributing to the identification of a 4.7 kb deletion in KANSL1 causing Koolen-de Vries syndrome. Hum. Mutat. 43, 1659–1665 (2022). (PMID: 3610487110.1002/humu.24467) Bick, D. et al. An online compendium of treatable genetic disorders. Am. J. Med. Genet. C 187, 48–54 (2021). (PMID: 10.1002/ajmg.c.31874) Capotondo, A. et al. Safety of arylsulfatase A overexpression for gene therapy of metachromatic leukodystrophy. Hum. Gene Ther. 18, 821–836 (2007). (PMID: 1784513010.1089/hum.2007.048) Feichtinger, R. G. et al. A spoonful of L-fucose-an efficient therapy for GFUS-CDG, a new glycosylation disorder. EMBO Mol. Med. 13, e14332 (2021). (PMID: 34468083842207810.15252/emmm.202114332) Tambuyzer, E. et al. Therapies for rare diseases: therapeutic modalities, progress and challenges ahead. Nat. Rev. Drug Discov. 19, 93–111 (2020). (PMID: 3183686110.1038/s41573-019-0049-9) Stark, Z. et al. Prospective comparison of the cost-effectiveness of clinical whole-exome sequencing with that of usual care overwhelmingly supports early use and reimbursement. Genet. Med. 19, 867–874 (2017). (PMID: 2812508110.1038/gim.2016.221) Retterer, K. et al. Clinical application of whole-exome sequencing across clinical indications. Genet. Med. 18, 696–704 (2016). (PMID: 2663354210.1038/gim.2015.148) Kingsmore, S. F. et al. A randomized, controlled trial of the analytic and diagnostic performance of singleton and trio, rapid genome and exome sequencing in ill infants. Am. J. Hum. Genet. 105, 719–733 (2019). (PMID: 31564432681753410.1016/j.ajhg.2019.08.009) Benito-Lozano, J. et al. Diagnostic process in rare diseases: determinants associated with diagnostic delay. Int. J. Environ. Res. Public Health 19, 6456 (2022). (PMID: 35682039918026410.3390/ijerph19116456) Benito-Lozano, J., López-Villalba, B., Arias-Merino, G., Posada de la Paz, M. & Alonso-Ferreira, V. Diagnostic delay in rare diseases: data from the Spanish rare diseases patient registry. Orphanet J. Rare Dis. 17, 418 (2022). (PMID: 36397119967037910.1186/s13023-022-02530-3) Illert, A. L. et al. The german network for personalized medicine to enhance patient care and translational research. Nat. Med. 29, 1298–1301 (2023). (PMID: 3728027610.1038/s41591-023-02354-z) Kaplanis, J. et al. Evidence for 28 genetic disorders discovered by combining healthcare and research data. Nature 586, 757–762 (2020). (PMID: 33057194711682610.1038/s41586-020-2832-5) Wright, C. F. et al. Evaluating variants classified as pathogenic in ClinVar in the DDD Study. Genet. Med. 23, 571–575 (2021). (PMID: 3314927610.1038/s41436-020-01021-9) Wright, C. F. et al. Making new genetic diagnoses with old data: iterative reanalysis and reporting from genome-wide data in 1,133 families with developmental disorders. Genet. Med. 20, 1216–1223 (2018). (PMID: 29323667591250510.1038/gim.2017.246) MacArthur, D. G. et al. Guidelines for investigating causality of sequence variants in human disease. Nature 508, 469–476 (2014). (PMID: 24759409418022310.1038/nature13127) Gao, Z., Waggoner, D., Stephens, M., Ober, C. & Przeworski, M. An estimate of the average number of recessive lethal mutations carried by humans. Genetics 199, 1243–1254 (2015). (PMID: 25697177439156010.1534/genetics.114.173351) Narasimhan, V. M. et al. Health and population effects of rare gene knockouts in adult humans with related parents. Science 352, 474–477 (2016). (PMID: 26940866498523810.1126/science.aac8624) Chakraborty, R. & Chakravarti, A. On consanguineous marriages and the genetic load. Hum. Genet. 36, 47–54 (1977). (PMID: 87041010.1007/BF00390435) La Rocca, L. A. et al. Understanding recessive disease risk in multi-ethnic populations with different degrees of consanguinity. Am. J. Med. Genet. A 194, e63452 (2024). (PMID: 3792156310.1002/ajmg.a.63452) Antonarakis, S. E. Carrier screening for recessive disorders. Nat. Rev. Genet. 20, 549–561 (2019). (PMID: 3114280910.1038/s41576-019-0134-2) Kalia, S. S. et al. Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics. Genet. Med. 19, 249–255 (2017). (PMID: 2785436010.1038/gim.2016.190) Rentzsch, P., Schubach, M., Shendure, J. & Kircher, M. CADD-splice-improving genome-wide variant effect prediction using deep learning-derived splice scores. Genome Med. 13, 31 (2021). (PMID: 33618777790110410.1186/s13073-021-00835-9) Peng, C. et al. CADA: phenotype-driven gene prioritization based on a case-enriched knowledge graph. NAR Genom. Bioinform. 3, lqab078 (2021). (PMID: 34514393841542910.1093/nargab/lqab078) Choukair, D. et al. An Integrated clinical pathway for diagnosis, treatment and care of rare diseases: model, operating procedures, and results of the project TRANSLATE-NAMSE funded by the German Federal Joint Committee. Orphanet J. Rare Dis. 16, 474 (2021). (PMID: 34772435858864010.1186/s13023-021-02092-w) Vasimuddin, M., Misra, S., Li, H. & Aluru, S. Efficient Architecture-Aware Acceleration of BWA-MEM for Multicore Systems. In 2019 IEEE International Parallel and Distributed Processing Symposium (IPDPS) 314–324 (IPDPS, 2019). Li, H. & Durbin, R. Fast and accurate short read alignment with Burrows–Wheeler transform. Bioinformatics 25, 1754–1760 (2009). (PMID: 19451168270523410.1093/bioinformatics/btp324) DePristo, M. A. et al. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat. Genet. 43, 491–498 (2011). (PMID: 21478889308346310.1038/ng.806) Li, H. A statistical framework for SNP calling, mutation discovery, association mapping and population genetical parameter estimation from sequencing data. Bioinformatics 27, 2987–2993 (2011). (PMID: 21903627319857510.1093/bioinformatics/btr509) Wagner, M. et al. Mitochondrial DNA mutation analysis from exome sequencing—a more holistic approach in diagnostics of suspected mitochondrial disease. J. Inherit. Metab. Dis. 42, 909–917 (2019). (PMID: 3105958510.1002/jimd.12109) Ye, K. et al. Split-read indel and structural variant calling using PINDEL. Methods Mol. Biol. 1833, 95–105 (2018). (PMID: 3003936610.1007/978-1-4939-8666-8_7) Plagnol, V. et al. A robust model for read count data in exome sequencing experiments and implications for copy number variant calling. Bioinformatics 28, 2747–2754 (2012). (PMID: 22942019347633610.1093/bioinformatics/bts526) McLaren, W. et al. The ensembl variant effect predictor. Genome Biol. 17, 122 (2016). (PMID: 27268795489382510.1186/s13059-016-0974-4) Jäger, M. et al. Jannovar: a java library for exome annotation. Hum. Mutat. 35, 548–555 (2014). (PMID: 2467761810.1002/humu.22531) Holtgrewe, M. et al. VarFish: comprehensive DNA variant analysis for diagnostics and research. Nucleic Acids Res. 48, W162–W169 (2020). (PMID: 32338743731946410.1093/nar/gkaa241) Pedersen, B. S. & Quinlan, A. R. Who’s who? Detecting and resolving sample anomalies in human DNA sequencing studies with Peddy. Am. J. Hum. Genet. 100, 406–413 (2017). (PMID: 28190455533908410.1016/j.ajhg.2017.01.017) Pemberton, T. J. et al. Genomic patterns of homozygosity in worldwide human populations. Am. J. Hum. Genet. 91, 275–292 (2012). (PMID: 22883143341554310.1016/j.ajhg.2012.06.014) Wang, S., Haynes, C., Barany, F. & Ott, J. Genome-wide autozygosity mapping in human populations. Genet. Epidemiol. 33, 172–180 (2009). (PMID: 18814273280285210.1002/gepi.20344) Narasimhan, V. et al. BCFtools/RoH: a hidden Markov model approach for detecting autozygosity from next-generation sequencing data. Bioinformatics 32, 1749–1751 (2016). (PMID: 26826718489241310.1093/bioinformatics/btw044) Richards, S. et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet. Med. 17, 405–424 (2015). (PMID: 25741868454475310.1038/gim.2015.30) Philippakis, A. A. et al. The MatchMaker Exchange: a platform for rare disease gene discovery. Hum. Mutat. 36, 915–921 (2015). (PMID: 26295439461000210.1002/humu.22858) Sobreira, N. L. M. et al. MatchMaker Exchange. Curr. Protoc. Hum. Genet. 95, 9.31.1–9.31.15 (2017). (PMID: 29044468) Karczewski, K. J. et al. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature 581, 434–443 (2020). (PMID: 32461654733419710.1038/s41586-020-2308-7) Samocha, K. E. et al. A framework for the interpretation of de novo mutation in human disease. Nat. Genet. 46, 944–950 (2014). (PMID: 25086666422218510.1038/ng.3050) R Core Team. R: a language and environment for statistical computing. R Project https://www.R-project.org/ (2021). Lieberwirth, J. et al. AutoCaSc: prioritizing candidate genes for neurodevelopmental disorders. Hum. Mutat. 43, 1795–1807 (2022). (PMID: 3599826110.1002/humu.24451) Strande, N. T. et al. Evaluating the clinical validity of gene–disease associations: an evidence-based framework developed by the Clinical Genome Resource. Am. J. Hum. Genet. 100, 895–906 (2017). (PMID: 28552198547373410.1016/j.ajhg.2017.04.015) Hustinx, A. et al. Improving deep facial phenotyping for ultra-rare disorder verification using model ensembles. In 2023 IEEE/CVF Winter Conference on Applications of Computer Vision (WACV) (IEEE, 2023). Schmidt, A. Code used for the analysis of the TRANSLATE-NAMSE data. Zenodo https://doi.org/10.5281/zenodo.10964188 (2024).
تواريخ الأحداث:	Date Created: 20240722 Latest Revision: 20240722
رمز التحديث:	20240723
DOI:	10.1038/s41588-024-01836-1
PMID:	39039281
قاعدة البيانات:	MEDLINE

Find this article in full text from Springer Verlag.

Full Text Finder

الوصف
تدمد:	1546-1718
DOI:	10.1038/s41588-024-01836-1