Journal Article

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

Weiß, Claudia, Kumar, Sheetal, Schlapakow, Elena, Knaus, Alexej, Cordula, Kiewert, Hentschel, Julia, Horn, Denise, Neugebauer, Julia, Kallinich, Tillmann, Reuner, Ulrike, Schuetz, Catharina, Tibelius, Alexandra, Engels, Hartmut, Schöls, Ludger J., Müller-Felber, Wolfgang, Krenn, Martin, Hüning, Irina, Klein, Christoph, Kubisch, Christian, Abou Jamra, Rami, Spielmann, Malte, Önder, Demet, Weiler-Normann, Christina, Hempel, Maja, Turro, Ernest, Schröck, Evelin, Schäfer, Valentin S., Castro-Gomez, Sergio, Bhasin, Meghna Ahuja, Klinkhammer, Hannah, Kornak, Uwe, Groffmann, Maximilian, Hellenbroich, Yorck, Bettendorf, Markus, Morawiec, Alexandra Marzena, Heinen, André, Grigull, Lorenz, Holzhauer, Susanne, Stoltenburg, Corinna, Rohlfs, Meino, Karakostas, Pantelis, Kaiser, Frank J., Westphal, Dominik S., Kuechler, Alma, Zawada, Michal, Rothoeft, Tobias, Lee-Kirsch, Min Ae, Hauck, Fabian, Schröder, Sebastian, Bevot, Andrea, Strehlow, Vincent, Bufler, Philip, Herget, Theresia, Kehrer, Martin, Aziz, Ahmad, Weigand, Heike, Brinkmann, Folke, Strom, Tim, Lesmann, Hellen, Boschann, Felix, Riess, Olaf, Bender, Tim, Sczakie

2024

Overview

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. Exome sequencing within a structured diagnostic process for rare diseases in Germany shows how facial image analysis and machine learning can guide variant prioritization and uncover many ultrarare diseases.

• Publisher: Nature Publishing Group US,Nature Publishing Group
• Subject: 45/23 / 692/308/2056 / 692/700/228/2050/1512 / Adolescent / Adult / Agriculture / Animal Genetics and Genomics / Biomedical and Life Sciences / Biomedicine / Cancer Research / Child / Child, Preschool / Data analysis / Diagnostic systems / Disorders / Exome Sequencing - methods / Female / Gene Function / Gene sequencing / Genetic Association Studies - methods / Genetic disorders / Genetic Testing - methods / Genotype & phenotype / Genotypes / Germany / Health care / Health care policy / High-Throughput Nucleotide Sequencing - methods / Human Genetics / Humans / Infant / Male / Multidisciplinary teams / Neurodevelopmental disorders / Neurodevelopmental Disorders - diagnosis / Neurodevelopmental Disorders - genetics / Next-generation sequencing / Patients / Phenotype / Phenotypes / Phenotyping / Prospective Studies / Rare diseases / Whole genome sequencing / Young Adult