期刊
GENETICS IN MEDICINE
卷 21, 期 1, 页码 161-172出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/s41436-018-0044-2
关键词
Exome sequencing; Genome sequencing; Undiagnosed diseases; Rare diseases; Phenotyping
资金
- National Institutes of Health (NIH) Common Fund through the Office of Strategic Coordination/Office of the NIH Director [U01HG007672]
Purpose: Sixty to seventy-five percent of individuals with rare and undiagnosed phenotypes remain undiagnosed after exome sequencing (ES). With standard ES reanalysis resolving 10-15% of the ES negatives, further approaches are necessary to maximize diagnoses in these individuals. Methods: In 38 ES negative patients an individualized genomic-phenotypic approach was employed utilizing (1) pheno-typing; (2) reanalyses of FASTQ files, with innovative bioinformatics; (3) targeted molecular testing; (4) genome sequencing (GS); and (5) conferring of clinical diagnoses when pathognomonic clinical findings occurred. Results: Certain and highly likely diagnoses were made in 18/38 (47%) individuals, including identifying two new developmental disorders. The majority of diagnoses (>70%) were due to our bioinformatics, phenotyping, and targeted testing identifying variants that were undetected or not prioritized on prior ES. GS diagnosed 3/18 individuals with structural variants not amenable to ES. Additionally, tentative diagnoses were made in 3 (8%), and in 5 individuals (13%) candidate genes were identified. Overall, diagnoses/potential leads were identified in 26/38 (68%). Conclusions: Our comprehensive approach to ES negatives maximizes the ES and clinical data for both diagnoses and candidate gene identification, without GS in the majority. This iterative approach is cost-effective and is pertinent to the current conundrum of ES negatives.
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