ArticleNature genetics2024
Next-generation phenotyping integrated in a national framework for patients with ultrarare disorders improves genetic diagnostics and yields new molecular findings.
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Article in Nature genetics, 2024. The graph could read no effect estimate from its abstract, so it casts no vote on the map. An erratum has been issued. Cited by 32 papers.
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32citing papers in PubMed
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Who cites it
32 citing papers in PubMed.
- Artificial intelligence in clinical genetics: Current practice and attitudes among the clinical genetics workforce.Genetics in medicine : official journal of the American College of Medical Genetics · 2026Article
- Machine Learning, Large Language Models, and Multimodal AI for Diagnosing Pediatric Rare Diseases: Scoping Review.Journal of medical Internet research · 2026Article
- Rare genetic variation in adults with surgically treated temporal lobe epilepsy: An exome sequencing study.Epilepsia open · 2026Article
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- Leveraging Next-Generation Phenotyping in Dysmorphology to Support Variant Interpretation in Mowat-Wilson Syndrome.Neurology. Genetics · 2026Article
- Artificial intelligence for pediatric rare disease diagnosis: a multimethod study integrating published evidence and clinician interviews.BMC medical informatics and decision making · 2026Article
- Trio analysis in dystonia identifies de novo KLC1 variants in a kinesinopathy with distinct motor and neurodevelopmental features.EBioMedicine · 2026Article
- Neurodevelopmental Disorder with Dystonia and Chorea Linked to De Novo Variants in the Splicing Regulator SRRM4.Movement disorders : official journal of the Movement Disorder Society · 2026Article
- JUND-driven stress-responsive astrocytes promote neuronal apoptosis via enhanced gap junction signaling in autism spectrum disorder.Molecular autism · 2026Article
- A novel spliceosomopathy caused by de novo SF3B3 variants.Genome medicine · 2026Article
- Addressing the diagnostic gap through deep phenotyping.Human genomics · 2026Article
- Loss-of-function variants in the CAPN1 activator CD99L2 cause X-linked spastic ataxia.Nature communications · 2026Article
- Article
- Biallelic TruncatingInternational journal of molecular sciences · 2026Review
- Privacy-by-Design with Federated Learning will drive future Rare Disease Research.Journal of neuromuscular diseases · 2026Review
- Clinical heterogeneity associated with Bardet-Biedl syndrome-related genes in presumed non-syndromic inherited retinal disease.Frontiers in cell and developmental biology · 2026Article
- Splice effect of a synonymous variant inHuman mutation · 2026Article
- Genomics in Health and Biomedicine.Advances in experimental medicine and biology · 2026Review
- Cracking the code: a head-to-head comparison of expert clinicians and artificial intelligence in diagnosing rare diseases.Orphanet journal of rare diseases · 2025Article
- Perspectives on the Current and Future State of Artificial Intelligence in Medical Genetics.American journal of medical genetics. Part A · 2025Review
Corrections and comments
- Erratum issued
Authors and funding
172 authors.
Axel Schmidt *Institute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.ORCID http://orcid.org/0000-0002-9780-7243
Magdalena Danyel *Institute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Kathrin Grundmann *Institute for Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Theresa Brunet *Institute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, München, Germany.ORCID http://orcid.org/0000-0002-5183-780X
Hannah KlinkhammerInstitute for Genomic Statistics and Bioinformatics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.ORCID http://orcid.org/0000-0003-3752-1275
Tzung-Chien HsiehInstitute for Genomic Statistics and Bioinformatics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.ORCID http://orcid.org/0000-0003-3828-4419
Hartmut EngelsInstitute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.ORCID http://orcid.org/0000-0003-1007-1809
Sophia PetersInstitute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.
Alexej KnausInstitute for Genomic Statistics and Bioinformatics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.ORCID http://orcid.org/0000-0003-0366-0533
Shahida MoosaInstitute for Medical Genetics, Stellenbosch University, Cape Town, South Africa.ORCID http://orcid.org/0000-0002-4463-3067
Luisa AverdunkDepartment of Pediatrics, University Hospital Düsseldorf, Düsseldorf, Germany.
Felix BoschannInstitute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Henrike Lisa SczakielInstitute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Sarina SchwartzmannInstitute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Martin Atta MensahInstitute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Jean Tori PantelInstitute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany.ORCID http://orcid.org/0000-0002-2674-4660
Manuel HoltgreweCore Uni Bioinformatics, Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Berlin, Germany.
Annemarie BöschDepartment of Pediatrics, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Claudia WeißDepartment of Pediatrics, Charité - Universitätsmedizin Berlin, Berlin, Germany.ORCID http://orcid.org/0000-0001-6167-5878
Natalie WeinholdDepartment of Pediatrics, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Aude-Annick SuterDepartment of Pediatrics, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Corinna StoltenburgDepartment of Pediatrics, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Julia NeugebauerDepartment of Pediatrics, Charité - Universitätsmedizin Berlin, Berlin, Germany.ORCID http://orcid.org/0000-0002-2576-1012
Tillmann KallinichDepartment of Pediatrics, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Angela M KaindlDepartment of Pediatric Neurology, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Susanne HolzhauerDepartment of Pediatrics, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Christoph BührerDepartment of Pediatrics, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Philip BuflerDepartment of Pediatrics, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Uwe KornakInstitute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany.ORCID http://orcid.org/0000-0002-4582-9838
Claus-Eric OttInstitute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany.ORCID http://orcid.org/0000-0003-3627-3791
Markus SchülkeInstitute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany.ORCID http://orcid.org/0000-0003-2824-3891
Hoa Huu Phuc NguyenDepartment of Human Genetics, Ruhr University Bochum, Bochum, Germany.
Sabine HoffjanDepartment of Human Genetics, Ruhr University Bochum, Bochum, Germany.
Corinna GrasemannDepartment of Pediatrics Bochum and CeSER, Ruhr University Bochum, Bochum, Germany.
Tobias RothoeftDepartment of Pediatrics Bochum and CeSER, Ruhr University Bochum, Bochum, Germany.
Folke BrinkmannDepartment of Pediatrics Bochum and CeSER, Ruhr University Bochum, Bochum, Germany.
Nora MatarDepartment of Pediatrics Bochum and CeSER, Ruhr University Bochum, Bochum, Germany.
Sugirthan SivalingamInstitute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.ORCID http://orcid.org/0000-0001-5239-5137
Claudia PerneInstitute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.
Elisabeth MangoldInstitute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.
Martina KreissInstitute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.
Kirsten CremerInstitute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.
Regina C BetzInstitute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.ORCID http://orcid.org/0000-0001-5024-3623
Martin MückeCenter for Rare Diseases, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.
Lorenz GrigullCenter for Rare Diseases, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.
Thomas KlockgetherDepartment of Neurology, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.
Isabel SpierInstitute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.
André HeimbachInstitute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.
Tim BenderCenter for Rare Diseases, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.
Fabian BrandInstitute for Genomic Statistics and Bioinformatics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.
Christiane StieberCenter for Rare Diseases, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.
Alexandra Marzena MorawiecCenter for Rare Diseases, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.
Pantelis KarakostasClinic for Internal Medicine III, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.
Valentin S SchäferClinic for Internal Medicine III, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.ORCID http://orcid.org/0000-0002-6591-5936
Sarah BernsenCenter for Rare Diseases, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.ORCID http://orcid.org/0000-0001-7485-2626
Patrick WeydtDepartment of Neurology, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.
Sergio Castro-GomezDepartment of Neurology, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.ORCID http://orcid.org/0000-0002-1581-474X
Ahmad AzizDepartment of Neurology, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.ORCID http://orcid.org/0000-0001-6184-458X
Marcus Grobe-EinslerDepartment of Neurology, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.
Okka KimmichDepartment of Neurology, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.
Xenia KobelevaDepartment of Neurology, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.
Demet ÖnderDepartment of Neurology, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.
Hellen LesmannInstitute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.
Sheetal KumarInstitute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.
Pawel TacikDepartment of Neurology, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.
Meghna Ahuja BhasinInstitute for Genomic Statistics and Bioinformatics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.
Pietro IncardonaInstitute for Genomic Statistics and Bioinformatics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.
Min Ae Lee-KirschUniversity Center for Rare Diseases, University Hospital Carl Gustav Carus, Dresden, Germany.
Reinhard BernerUniversity Center for Rare Diseases, University Hospital Carl Gustav Carus, Dresden, Germany.
Catharina SchuetzUniversity Center for Rare Diseases, University Hospital Carl Gustav Carus, Dresden, Germany.
Julia KörholzUniversity Center for Rare Diseases, University Hospital Carl Gustav Carus, Dresden, Germany.
Tanita KretschmerUniversity Center for Rare Diseases, University Hospital Carl Gustav Carus, Dresden, Germany.
Nataliya Di DonatoUniversity Center for Rare Diseases, University Hospital Carl Gustav Carus, Dresden, Germany.ORCID http://orcid.org/0000-0001-9439-4677
Evelin SchröckUniversity Center for Rare Diseases, University Hospital Carl Gustav Carus, Dresden, Germany.ORCID http://orcid.org/0000-0002-3377-1704
André HeinenUniversity Center for Rare Diseases, University Hospital Carl Gustav Carus, Dresden, Germany.
Ulrike ReunerUniversity Center for Rare Diseases, University Hospital Carl Gustav Carus, Dresden, Germany.
Amalia-Mihaela HanßkeUniversity Center for Rare Diseases, University Hospital Carl Gustav Carus, Dresden, Germany.
Frank J KaiserInstitute of Human Genetics, University Hospital Essen, Essen, Germany.
Eva MankaDepartment of Pediatrics II, University Hospital Essen, Essen, Germany.
Martin MunteanuInstitute of Human Genetics, University Hospital Essen, Essen, Germany.
Alma KuechlerInstitute of Human Genetics, University Hospital Essen, Essen, Germany.
Kiewert CordulaDepartment of Pediatrics II, University Hospital Essen, Essen, Germany.
Raphael HirtzDepartment of Pediatrics II, University Hospital Essen, Essen, Germany.
Elena SchlapakowDepartment of Neurology, University Hospital Halle, Halle, Germany.
Christian SchleinInstitute of Human Genetics, University Hospital Hamburg-Eppendorf, Hamburg, Germany.ORCID http://orcid.org/0000-0002-2791-1790
Jasmin LisfeldInstitute of Human Genetics, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Christian KubischInstitute of Human Genetics, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Theresia HergetInstitute of Human Genetics, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Maja HempelInstitute of Human Genetics, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Christina Weiler-NormannMartin Zeitz Center for Rare Diseases, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Kurt UllrichMartin Zeitz Center for Rare Diseases, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Christoph SchrammMartin Zeitz Center for Rare Diseases, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Cornelia RudolphMartin Zeitz Center for Rare Diseases, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Franziska RilligMartin Zeitz Center for Rare Diseases, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Maximilian GroffmannMartin Zeitz Center for Rare Diseases, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Ania MuntauDepartment of Pediatrics, University Hospital Hamburg-Eppendorf, Hamburg, Germany.
Alexandra TibeliusInstitute of Human Genetics, Heidelberg University, Heidelberg, Germany.
Eva M C SchwaiboldInstitute of Human Genetics, Heidelberg University, Heidelberg, Germany.ORCID http://orcid.org/0000-0003-2708-9642
Christian P SchaafInstitute of Human Genetics, Heidelberg University, Heidelberg, Germany.
Michal ZawadaInstitute of Human Genetics, Heidelberg University, Heidelberg, Germany.
Lilian KaufmannInstitute of Human Genetics, Heidelberg University, Heidelberg, Germany.
Katrin HinderhoferInstitute of Human Genetics, Heidelberg University, Heidelberg, Germany.
Pamela M OkunCenter for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.ORCID http://orcid.org/0000-0001-9981-8918
Urania KotzaeridouCenter for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.
Georg F HoffmannCenter for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.
Daniela ChoukairCenter for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.
Markus BettendorfCenter for Child and Adolescent Medicine, University Hospital Heidelberg, Heidelberg, Germany.
Malte SpielmannInstitute of Human Genetics, University Hospital Schleswig-Holstein, Lübeck, Germany.ORCID http://orcid.org/0000-0002-0583-4683
Annekatrin RipkeCenter for Rare Diseases, University Hospital Schleswig-Holstein, Lübeck, Germany.
Martje PaulyDepartment of Neurology, University Hospital Schleswig-Holstein, Lübeck, Germany.ORCID http://orcid.org/0000-0002-7794-0282
Alexander MünchauCenter for Rare Diseases, University Hospital Schleswig-Holstein, Lübeck, Germany.
Katja LohmannInstitute of Neurogenetics, University of Lübeck, Lübeck, Germany.ORCID http://orcid.org/0000-0002-5121-1460
Irina HüningInstitute of Human Genetics, University Hospital Schleswig-Holstein, Lübeck, Germany.
Britta HankerInstitute of Human Genetics, University of Lübeck, Lübeck, Germany.
Tobias BäumerCenter for Rare Diseases, University Hospital Schleswig-Holstein, Lübeck, Germany.
Rebecca HerzogCenter for Rare Diseases, University Hospital Schleswig-Holstein, Lübeck, Germany.ORCID http://orcid.org/0000-0002-5906-5947
Yorck HellenbroichDepartment of Human Genetics, University Hospital Schleswig-Holstein, Lübeck, Germany.
Dominik S WestphalInstitute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, München, Germany.ORCID http://orcid.org/0000-0003-4870-9863
Tim StromInstitute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, München, Germany.
Reka KovacsInstitute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, München, Germany.
Korbinian M RiedhammerInstitute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, München, Germany.ORCID http://orcid.org/0000-0002-7503-5801
Katharina MayerhanserInstitute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, München, Germany.
Elisabeth GrafInstitute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, München, Germany.
Melanie BruggerInstitute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, München, Germany.ORCID http://orcid.org/0000-0002-6920-8550
Julia HoefeleInstitute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, München, Germany.
Konrad OexleInstitute of Neurogenomics, Helmholtz Zentrum München, München, Germany.
Nazanin Mirza-SchreiberInstitute of Neurogenomics, Helmholtz Zentrum München, München, Germany.ORCID http://orcid.org/0000-0003-0836-8267
Riccardo BeruttiInstitute of Neurogenomics, Helmholtz Zentrum München, München, Germany.ORCID http://orcid.org/0000-0003-1862-3700
Ulrich SchatzInstitute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, München, Germany.
Martin KrennInstitute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, München, Germany.
Christine MakowskiDepartment of Paediatrics, Adolescent Medicine and Neonatology, München, Germany.
Heike WeigandDr. von Hauner Children's Hospital, University Hospital Munich, München, Germany.
Sebastian SchröderDr. von Hauner Children's Hospital, University Hospital Munich, München, Germany.
Meino RohlfsDr. von Hauner Children's Hospital, University Hospital Munich, München, Germany.
Katharina VillDr. von Hauner Children's Hospital, University Hospital Munich, München, Germany.
Fabian HauckDr. von Hauner Children's Hospital, University Hospital Munich, München, Germany.ORCID http://orcid.org/0000-0001-9644-2003
Ingo BorggraefeDr. von Hauner Children's Hospital, University Hospital Munich, München, Germany.ORCID http://orcid.org/0000-0002-8484-5945
Wolfgang Müller-FelberDr. von Hauner Children's Hospital, University Hospital Munich, München, Germany.
Ingo KurthInstitute for Human Genetics and Genomic Medicine, Medical Faculty, Uniklinik RWTH Aachen University, Aachen, Germany.ORCID http://orcid.org/0000-0002-5642-8378
Miriam ElbrachtInstitute for Human Genetics and Genomic Medicine, Medical Faculty, Uniklinik RWTH Aachen University, Aachen, Germany.ORCID http://orcid.org/0000-0001-5088-1369
Cordula KnoppInstitute for Human Genetics and Genomic Medicine, Medical Faculty, Uniklinik RWTH Aachen University, Aachen, Germany.
Matthias BegemannInstitute for Human Genetics and Genomic Medicine, Medical Faculty, Uniklinik RWTH Aachen University, Aachen, Germany.ORCID http://orcid.org/0000-0002-4659-8437
Florian KraftInstitute for Human Genetics and Genomic Medicine, Medical Faculty, Uniklinik RWTH Aachen University, Aachen, Germany.ORCID http://orcid.org/0000-0002-5324-9155
Johannes R LemkeInstitute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.ORCID http://orcid.org/0000-0002-4435-6610
Julia HentschelInstitute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
Konrad PlatzerInstitute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.ORCID http://orcid.org/0000-0001-6127-6308
Vincent StrehlowInstitute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.
Rami Abou JamraInstitute of Human Genetics, University of Leipzig Medical Center, Leipzig, Germany.ORCID http://orcid.org/0000-0002-1542-1399
Martin KehrerInstitute for Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
German DemidovInstitute for Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.ORCID http://orcid.org/0000-0001-9075-4276
Stefanie Beck-WödlInstitute for Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
Holm GraessnerCenter for Rare Diseases, University of Tübingen, Tübingen, Germany.
Marc SturmInstitute for Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.ORCID http://orcid.org/0000-0002-6552-8362
Lena ZeltnerCenter for Rare Diseases, University of Tübingen, Tübingen, Germany.
Ludger J SchölsDepartment of Neurology, University of Tübingen, Tübingen, Germany.
Janine MaggCenter for Rare Diseases, University of Tübingen, Tübingen, Germany.
Andrea BevotDepartment of Pediatric Neurology and Developmental Medicine, University of Tübingen, Tübingen, Germany.
Christiane KehrerDepartment of Pediatric Neurology and Developmental Medicine, University of Tübingen, Tübingen, Germany.
Nadja KaiserDepartment of Pediatric Neurology and Developmental Medicine, University of Tübingen, Tübingen, Germany.
Ernest TurroDepartment of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.ORCID http://orcid.org/0000-0002-1820-6563
Denise HornInstitute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Annette Grüters-KieslichBerlin Centre for Rare Diseases, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Christoph KleinDr. von Hauner Children's Hospital, University Hospital Munich, München, Germany.ORCID http://orcid.org/0000-0003-0956-0445
Stefan MundlosInstitute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Markus NöthenInstitute of Human Genetics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany.ORCID http://orcid.org/0000-0002-8770-2464
Olaf RiessInstitute for Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.ORCID http://orcid.org/0000-0002-7011-1369
Thomas MeitingerInstitute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, München, Germany.ORCID http://orcid.org/0000-0002-8838-8403
Heiko KrudeBerlin Centre for Rare Diseases, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Peter M KrawitzInstitute for Genomic Statistics and Bioinformatics, University of Bonn, Medical Faculty and University Hospital Bonn, Bonn, Germany. pkrawitz@uni-bonn.de.ORCID http://orcid.org/0000-0002-3194-8625
Tobias HaackInstitute for Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.ORCID http://orcid.org/0000-0001-6033-4836
Nadja EhmkeInstitute for Medical Genetics and Human Genetics, Charité - Universitätsmedizin Berlin, Berlin, Germany.
Matias WagnerInstitute of Human Genetics, Klinikum rechts der Isar, School of Medicine, Technical University of Munich, München, Germany.
Funding
Integrative analysis of whole genomes and transcriptomes from multiple cell types in rare disease patientsR01HL161365 · NHLBI · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI Ernest Turro · 2023 to 2026
$2.6MBayesian genetic association analysis of all rare diseases in the Kids First cohortR03HD111492 · NICHD · ICAHN SCHOOL OF MEDICINE AT MOUNT SINAI · PI TURRO, ERNEST · 2023 to 2024
$338kNHLBI NIH HHS R01 HL161365NICHD NIH HHS R03 HD111492
Abstract
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.
Indexed as
High-Throughput Nucleotide SequencingPhenotypeAdolescentAdultChildChild, PreschoolExome SequencingFemaleGenetic Association StudiesGenetic TestingGermanyHumansInfantMaleNeurodevelopmental DisordersProspective Studies
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the Socratic graph.