Next-generation phenotyping integrated in a national framework for patients with ultrarare disorders improves genetic diagnostics and yields new molecular findings
Research output: Contribution to journal › Research article › Contributed
Contributors
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.
Details
Original language | English |
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Pages (from-to) | 1644-1653 |
Number of pages | 10 |
Journal | Nature genetics |
Volume | 56 |
Issue number | 8 |
Publication status | Published - Aug 2024 |
Peer-reviewed | No |
External IDs
PubMedCentral | PMC11319204 |
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Scopus | 85199186684 |
ORCID | /0009-0003-6519-0482/work/166325416 |
ORCID | /0000-0001-6313-4434/work/166326575 |
Keywords
Keywords
- Humans, Phenotype, Female, Male, High-Throughput Nucleotide Sequencing/methods, Child, Germany, Exome Sequencing/methods, Adolescent, Genetic Association Studies/methods, Genetic Testing/methods, Child, Preschool, Prospective Studies, Adult, Neurodevelopmental Disorders/genetics, Infant, Young Adult