Exome sequencing has higher diagnostic yield compared to simulated disease-specific panels in children with suspected monogenic disorders
| Autor: | Susan M. White, Natalie P. Thorne, Sebastian Lunke, Clara Gaff, Alison Yeung, Tiong Yang Tan, Oliver James Dillon, Zornitza Stark |
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| Rok vydání: | 2018 |
| Předmět: |
Male
0301 basic medicine Disease specific Candidate gene Pediatrics medicine.medical_specialty Adolescent Article 03 medical and health sciences Gene panel Exome Sequencing Genetics medicine Humans Exome Genetic Testing Medical diagnosis Child Genetics (clinical) Exome sequencing Genetic testing medicine.diagnostic_test business.industry Genetic heterogeneity Genetic Diseases Inborn Sequence Analysis DNA Phenotype 030104 developmental biology Child Preschool Mutation Female business |
| Zdroj: | European Journal of Human Genetics. 26:644-651 |
| ISSN: | 1476-5438 1018-4813 |
| Popis: | As test costs decline, whole-exome sequencing (WES) has become increasingly used for clinical diagnosis, and now represents the primary alternative to gene panel testing for patients with a suspected genetic disorder. We sought to compare the diagnostic yield of singleton-WES with simulated application of commercial gene panels in children suspected of having a genetically heterogeneous condition. Recruitment, singleton-WES and phenotype-driven variant analysis was completed for 145 paediatric patients. At recruitment, clinicians were required to propose commercial gene panel tests as an alternative to WES and nominate a phenotype-driven candidate gene list. In WES-diagnosed children, three commercial options for each proposed panel were identified and evaluated for hypothetical diagnostic yield assuming 100% analytical sensitivity and specificity. We compared the price of WES with the least costly panel in WES-diagnosed children. In WES-undiagnosed children, we evaluated the exonic coverage of their phenotype-driven gene list using aggregate data. WES diagnoses were made in genes not included in at least one-of-three commercial panels in 42% of cases. Had a panel been selected instead, 23% of WES-diagnosed children would not have been diagnosed. In 26% of cases, the least costly panel option would have been more expensive than WES. Evaluation of WES coverage found that at the most stringent level of 20× coverage, the likelihood of missing a clinically relevant variant in a candidate gene list was maximally 8%. The broader coverage of WES makes it a superior alternative to gene panel testing at similar financial cost for children with suspected complex monogenic phenotypes. |
| Databáze: | OpenAIRE |
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