Back to Search
Start Over
Actionable exomic incidental findings in 6503 participants: challenges of variant classification
- Source :
- Genome research, vol 25, iss 3
- Publication Year :
- 2015
-
Abstract
- Recommendations for laboratories to report incidental findings from genomic tests have stimulated interest in such results. In order to investigate the criteria and processes for assigning the pathogenicity of specific variants and to estimate the frequency of such incidental findings in patients of European and African ancestry, we classified potentially actionable pathogenic single-nucleotide variants (SNVs) in all 4300 European- and 2203 African-ancestry participants sequenced by the NHLBI Exome Sequencing Project (ESP). We considered 112 gene-disease pairs selected by an expert panel as associated with medically actionable genetic disorders that may be undiagnosed in adults. The resulting classifications were compared to classifications from other clinical and research genetic testing laboratories, as well as with in silico pathogenicity scores. Among European-ancestry participants, 30 of 4300 (0.7%) had a pathogenic SNV and six (0.1%) had a disruptive variant that was expected to be pathogenic, whereas 52 (1.2%) had likely pathogenic SNVs. For African-ancestry participants, six of 2203 (0.3%) had a pathogenic SNV and six (0.3%) had an expected pathogenic disruptive variant, whereas 13 (0.6%) had likely pathogenic SNVs. Genomic Evolutionary Rate Profiling mammalian conservation score and the Combined Annotation Dependent Depletion summary score of conservation, substitution, regulation, and other evidence were compared across pathogenicity assignments and appear to have utility in variant classification. This work provides a refined estimate of the burden of adult onset, medically actionable incidental findings expected from exome sequencing, highlights challenges in variant classification, and demonstrates the need for a better curated variant interpretation knowledge base.
- Subjects :
- Adult
Male
Bioinformatics
In silico
Black People
Genomics
Biology
Genome
Medical and Health Sciences
Polymorphism, Single Nucleotide
White People
Gene Frequency
Clinical Research
medicine
Genetics
Humans
Dominant
Exome
Genetic Testing
Polymorphism
Allele frequency
Genetics (clinical)
Exome sequencing
Genetic Association Studies
Genetic testing
Genes, Dominant
Incidental Findings
medicine.diagnostic_test
Whites
Genome, Human
Research
Human Genome
High-Throughput Nucleotide Sequencing
Single Nucleotide
Blacks
Biological Sciences
Good Health and Well Being
Phenotype
Genes
Human genome
Female
Human
Biotechnology
Subjects
Details
- ISSN :
- 15495469
- Volume :
- 25
- Issue :
- 3
- Database :
- OpenAIRE
- Journal :
- Genome research
- Accession number :
- edsair.doi.dedup.....5c2fc9c7cff920a0129002fba37c9ae5