期刊
GENETICS IN MEDICINE
卷 20, 期 10, 页码 1216-1223出版社
ELSEVIER SCIENCE INC
DOI: 10.1038/gim.2017.246
关键词
diagnostic yield; exome sequencing; reanalysis; reclassification; recontact
资金
- Health Innovation Challenge Fund [HICF-1009-003]
- Wellcome Trust [200990/Z/16/Z]
- Department of Health
- Wellcome Trust Sanger Institute [WT098051]
- National Institute for Health Research, through the Comprehensive Clinical Research Network
- Wellcome Trust [200990/Z/16/Z] Funding Source: Wellcome Trust
- MRC [MC_PC_U127561093, MC_UU_00007/3] Funding Source: UKRI
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.
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