期刊
GENETICS IN MEDICINE
卷 19, 期 5, 页码 593-598出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/gim.2016.155
关键词
autozygome; clinical genomics; clinical exome; clinical genome; variant interpretation
资金
- KACST grants [13-BIO1113-20]
- KSCDR
Background: Clinical exome sequencing (CES) has greatly improved the diagnostic process for individuals with suspected genetic disorders. However, the majority remains undiagnosed after CES. Although understanding potential reasons for this limited sensitivity is critical for improving the delivery of clinical genomics, research in this area has been limited. Materials and Methods: We first calculated the theoretical maximum sensitivity of CES by analyzing >100 families in whom a Mendelian phenotype is mapped to a single locus. We then tested the hypothesis that positional mapping can limit the search space and thereby facilitate variant interpretation by reanalyzing 33 families with negative CES and applying positional mapping. Results: We found that >95% of families who map to a single locus harbored genic (as opposed to intergenic) variants that are potentially identifiable by CES. Our reanalysis of negative CES revealed likely causal variants in the majority (88%). Several of these solved cases have undergone negative whole-genome sequencing. Conclusion: The discrepancy between the theoretical maximum and the actual clinical sensitivity of CES is primarily in the variant filtration rather than the variant capture and sequencing phase. The solution to negative CES is not necessarily in expanding the coverage but rather in devising approaches that improve variant filtration. We suggest that positional mapping is one such approach.
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