Enhanced utility of family-centered diagnostic exome sequencing with inheritance model-based analysis: results from 500 unselected families with undiagnosed genetic conditions
| Autor: | Zöe Powis, Charles Dunlop, Sha Tang, Hong Lu, Elizabeth C. Chao, Xiang Li, Hsiao-Mei Lu, David Ruble, Aaron Elliott, Dima El-Khechen, Monica Lao, Cameron Mroske, Kelly D. Farwell, Melissa C. Parra, Stephanie K. Gandomi, Jennifer Wen, Brigette Tippin Davis, Soren Fischbach, Ruth M. Baxter, Ira Lu, David J. Salvador, Layla Shahmirzadi, Shela Lee, Wenqi Zeng |
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| Předmět: |
Adult
Male Proband Pediatrics medicine.medical_specialty Heredity Ataxia Sequence analysis Disease medicine.disease_cause Cohort Studies Databases Genetic Humans Medicine Exome Genetics (clinical) Exome sequencing business.industry Sequence Analysis DNA Molecular Diagnostic Techniques Female medicine.symptom business Cohort study |
| Zdroj: | Europe PubMed Central |
| Popis: | Diagnostic exome sequencing was immediately successful in diagnosing patients in whom traditional technologies were uninformative. Herein, we provide the results from the first 500 probands referred to a clinical laboratory for diagnostic exome sequencing. Family-based exome sequencing included whole-exome sequencing followed by family inheritance−based model filtering, comprehensive medical review, familial cosegregation analysis, and analysis of novel genes. A positive or likely positive result in a characterized gene was identified in 30% of patients (152/500). A novel gene finding was identified in 7.5% of patients (31/416). The highest diagnostic rates were observed among patients with ataxia, multiple congenital anomalies, and epilepsy (44, 36, and 35%, respectively). Twenty-three percent of positive findings were within genes characterized within the past 2 years. The diagnostic rate was significantly higher among families undergoing a trio (37%) as compared with a singleton (21%) whole-exome testing strategy. Overall, we present results from the largest clinical cohort of diagnostic exome sequencing cases to date. These data demonstrate the utility of family-based exome sequencing and analysis to obtain the highest reported detection rate in an unselected clinical cohort, illustrating the utility of diagnostic exome sequencing as a transformative technology for the molecular diagnosis of genetic disease. Genet Med 17 7, 578–586. |
| Databáze: | OpenAIRE |
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