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Reducing diagnostic turnaround times of exome sequencing for families requiring timely diagnoses |
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| Institution: | 1. Department of Pediatrics, Stanford University, Stanford, California, USA;2. Department of Computer Science, Stanford University, Stanford, California, USA;3. Department of Developmental Biology, Stanford University, Stanford, California, USA;1. Institute of Human Genetics, University of Heidelberg, Im Neuenheimer Feld 366, 69120 Heidelberg, Germany;2. Department of General Pediatrics, Division of Neuropediatrics and Metabolic Medicine, University Hospital Heidelberg, Im Neuenheimer Feld 430, 69120 Heidelberg, Germany;3. Medical Faculty Heidelberg, Heidelberg University, 69120 Heidelberg, Germany;4. Division of Theoretical Bioinformatics, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany;5. Genomics & Proteomics Core Facility, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 580, 69120 Heidelberg, Germany;6. Department for Bioinformatics and Functional Genomics, Institute for Pharmacy and Molecular Biotechnology (IPMB) and BioQuant, Heidelberg University, 69120 Heidelberg, Germany;1. Clinic for Special Children, Strasburg, Pennsylvania, USA;;2. Regeneron Genetics Center, Regeneron Pharmaceuticals Inc., Tarrytown, New York, USA;;3. Department of Biology, Franklin & Marshall College, Lancaster, Pennsylvania, USA.;1. Victorian Clinical Genetics Services, Murdoch Children’s Research Institute, Melbourne, Australia;2. Melbourne Genomics Health Alliance, Melbourne, Australia;3. Department of Paediatrics, University of Melbourne, Melbourne, Australia;4. Monash Genetics, Monash Children’s Hospital, Melbourne, Australia;5. Department of Paediatrics, Monash University Melbourne Australia;6. Centre for Healthcare Resilience and Implementation Science, Australian Institute of Health Innovation, Macquarie University Melbourne Australia;7. Department of Medicine, University of Melbourne Melbourne Australia |
| Abstract: | Background and objectiveWhole-exome sequencing (WES) has now entered medical practice with powerful applications in the diagnosis of rare Mendelian disorders. Although the usefulness and cost-effectiveness of WES have been widely demonstrated, it is essential to reduce the diagnostic turnaround time to make WES a first-line procedure. Since 2011, the automation of laboratory procedures and advances in sequencing chemistry have made it possible to carry out diagnostic whole genome sequencing from the blood sample to molecular diagnosis of suspected genetic disorders within 50 h. Taking advantage of these advances, the main objective of the study was to improve turnaround times for sequencing results.MethodsWES was proposed to 29 patients with severe undiagnosed disorders with developmental abnormalities and faced with medical situations requiring rapid diagnosis. Each family gave consent. The extracted DNA was sequenced on a NextSeq500 (Illumina) instrument. Data were analyzed following standard procedures. Variants were interpreted using in-house software. Each rare variant affecting protein sequences with clinical relevance was tested for familial segregation.ResultsThe diagnostic rate was 45% (13/29), with a mean turnaround time of 40 days from reception of the specimen to delivery of results to the referring physician. Besides permitting genetic counseling, the rapid diagnosis for positive families led to two pre-natal diagnoses and two inclusions in clinical trials.ConclusionsThis pilot study demonstrated the feasibility of rapid diagnostic WES in our primary genetics center. It reduced the diagnostic odyssey and helped provide support to families. |
| Keywords: | Exome sequencing Diagnostic turnaround time Undiagnosed genetic conditions WES"} {"#name":"keyword" "$":{"id":"kwrd0030"} "$$":[{"#name":"text" "_":"Whole Exome Sequencing WGS"} {"#name":"keyword" "$":{"id":"kwrd0040"} "$$":[{"#name":"text" "_":"Whole Genome Sequencing ID"} {"#name":"keyword" "$":{"id":"kwrd0050"} "$$":[{"#name":"text" "_":"Intellectual Deficiency |
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