Journal article
Making new genetic diagnoses with old data: iterative reanalysis and reporting from genome-wide data in 1,133 families with developmental disorders
- Abstract:
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Purpose
Given the rapid pace of discovery in rare disease genomics, it is likely that improvements in diagnostic yield can be made by systematically reanalyzing previously generated genomic sequence data in light of new knowledge.
Methods
We tested this hypothesis in the United Kingdom–wide Deciphering Developmental Disorders study, where in 2014 we reported a diagnostic yield of 27% through whole-exome sequencing of 1,133 children with severe developmental disorders and their parents. We reanalyzed existing data using improved variant calling methodologies, novel variant detection algorithms, updated variant annotation, evidence-based filtering strategies, and newly discovered disease-associated genes.
Results
We are now able to diagnose an additional 182 individuals, taking our overall diagnostic yield to 454/1,133 (40%), and another 43 (4%) have a finding of uncertain clinical significance. The majority of these new diagnoses are due to novel developmental disorder–associated genes discovered since our original publication.
Conclusion
This study highlights the importance of coupling large-scale research with clinical practice, and of discussing the possibility of iterative reanalysis and recontact with patients and health professionals at an early stage. We estimate that implementing parent–offspring whole-exome sequencing as a first-line diagnostic test for developmental disorders would diagnose >50% of patients.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Version of record, pdf, 3.0MB, Terms of use)
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- Publisher copy:
- 10.1038/gim.2017.246
Authors
- Publisher:
- Nature Publishing Group
- Journal:
- Genetics in Medicine More from this journal
- Volume:
- 20
- Issue:
- 10
- Pages:
- 1216–1223
- Publication date:
- 2018-01-11
- Acceptance date:
- 2017-11-20
- DOI:
- EISSN:
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1530-0366
- ISSN:
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1098-3600
- Keywords:
- Pubs id:
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pubs:800947
- UUID:
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uuid:d59c74a1-2e49-4bef-8516-0d600309367c
- Local pid:
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pubs:800947
- Source identifiers:
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800947
- Deposit date:
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2017-11-29
- ARK identifier:
Terms of use
- Copyright holder:
- Wright et al, American College of Medical Genetics and Genomics
- Copyright date:
- 2018
- Notes:
- © The Author(s) 2018 © American College of Medical Genetics and Genomics. This work is licensed under a Creative Commons Attribution 4.0 International License. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in the credit line; if the material is not included under the Creative Commons license, users will need to obtain permission from the license holder to reproduce the material.
- Licence:
- CC Attribution (CC BY)
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