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

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...

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Main Authors: Schmidt, Axel (Author) , Danyel, Magdalena (Author) , Grundmann-Hauser, Kathrin (Author) , Brunet, Theresa (Author) , Klinkhammer, Hannah (Author) , Hsieh, Tzung-Chien (Author) , Engels, Hartmut (Author) , Schlapakow, Elena (Author) , Hempel, Maja (Author) , Tibelius, Alexandra (Author) , Schwaibold, Eva (Author) , Schaaf, Christian P. (Author) , Zawada, Michal (Author) , Kaufmann, Lilian (Author) , Hinderhofer, Katrin (Author) , Okun, Pamela M. (Author) , Kotzaeridou, Urania (Author) , Hoffmann, Georg F. (Author) , Choukair, Daniela (Author) , Bettendorf, Markus (Author)
Format: Article (Journal)
Language:English
Published: 22 July 2024
In: Nature genetics
Year: 2024, Volume: 56, Issue: 8, Pages: 1644-1653, [1-8]
ISSN:1546-1718
DOI:10.1038/s41588-024-01836-1
Online Access:Resolving-System, kostenfrei: https://doi.org/10.1038/s41588-024-01836-1
Resolving-System, kostenfrei: https://doi.org/10.25673/117968
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Author Notes:Axel Schmidt, Magdalena Danyel, Kathrin Grundmann, Theresa Brunet, Hannah Klinkhammer, Tzung-Chien Hsieh, Hartmut Engels, Elena Schlapakow, Maja Hempel, Alexandra Tibelius, Eva M.C. Schwaibold, Christian P. Schaaf, Michal Zawada, Lilian Kaufmann, Katrin Hinderhofer, Pamela M. Okun, Urania Kotzaeridou, Georg F. Hoffmann, Daniela Choukair, Markus Bettendorf ... [und viele weitere]
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Summary: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.
Item Description:Veröffentlicht: 22. Juli 2024
Gesehen am 11.11.2025
Physical Description:Online Resource
ISSN:1546-1718
DOI:10.1038/s41588-024-01836-1

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