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Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test.
- Source :
-
Genetics in medicine : official journal of the American College of Medical Genetics [Genet Med] 2018 Apr; Vol. 20 (4), pp. 435-443. Date of Electronic Publication: 2017 Aug 03. - Publication Year :
- 2018
-
Abstract
- PurposeGenetic testing is an integral diagnostic component of pediatric medicine. Standard of care is often a time-consuming stepwise approach involving chromosomal microarray analysis and targeted gene sequencing panels, which can be costly and inconclusive. Whole-genome sequencing (WGS) provides a comprehensive testing platform that has the potential to streamline genetic assessments, but there are limited comparative data to guide its clinical use.MethodsWe prospectively recruited 103 patients from pediatric non-genetic subspecialty clinics, each with a clinical phenotype suggestive of an underlying genetic disorder, and compared the diagnostic yield and coverage of WGS with those of conventional genetic testing.ResultsWGS identified diagnostic variants in 41% of individuals, representing a significant increase over conventional testing results (24%; Pā=ā0.01). Genes clinically sequenced in the cohort (nā=ā1,226) were well covered by WGS, with a median exonic coverage of 40 × ±8 × (mean ±SD). All the molecular diagnoses made by conventional methods were captured by WGS. The 18 new diagnoses made with WGS included structural and non-exonic sequence variants not detectable with whole-exome sequencing, and confirmed recent disease associations with the genes PIGG, RNU4ATAC, TRIO, and UNC13A.ConclusionWGS as a primary clinical test provided a higher diagnostic yield than conventional genetic testing in a clinically heterogeneous cohort.
- Subjects :
- Computational Biology methods
DNA Copy Number Variations
Exome
Female
Genetic Variation
Humans
Male
Molecular Sequence Annotation
Phenotype
Exome Sequencing methods
Exome Sequencing standards
Genetic Association Studies methods
Genetic Association Studies standards
Genetic Diseases, Inborn diagnosis
Genetic Diseases, Inborn genetics
Genetic Predisposition to Disease
Genetic Testing methods
Genetic Testing standards
Sequence Analysis, DNA methods
Sequence Analysis, DNA standards
Whole Genome Sequencing methods
Whole Genome Sequencing standards
Subjects
Details
- Language :
- English
- ISSN :
- 1530-0366
- Volume :
- 20
- Issue :
- 4
- Database :
- MEDLINE
- Journal :
- Genetics in medicine : official journal of the American College of Medical Genetics
- Publication Type :
- Academic Journal
- Accession number :
- 28771251
- Full Text :
- https://doi.org/10.1038/gim.2017.119