Look before you leap, and list before you look: the use of a priori curated gene lists to guide exome analysis. B. C. Powell1, A. K. M. Foreman1, J. M. O'Daniel1, K. Lee1, L. Boshe1, K. R. Crooks2, M. Lu2, Z. Fan3, J. K. Booker2, K. E. Weck2, J. P. Evans1, J. S. Berg1 1) Department of Genetics, University of North Carolina at Chapel Hill, Chapel Hill, NC; 2) Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC; 3) Department of Neurology, University of North Carolina at Chapel Hill, Chapel Hill, NC.
The application of genome-scale clinical genetic testing inevitably generates large numbers of variants of uncertain clinical significance. Evaluating these numerous variants can greatly complicate and prolong variant adjudication. To avoid undertaking substantial duplication of effort in an already time-intensive endeavor, molecular analysts need a structured way to store and query their evaluation of literature regarding the clinical impact of variants on specific genes. The NCGENES project (North Carolina Clinical Genomic Evaluation by NextGen Exome Sequencing) mitigates these challenges through systematic curation of a priori-determined sets of genes associated with the clinical signs or symptoms that comprise the indication for testing. Constraining the hypothesis of which genes are regarded as clinically-relevant for a presenting phenotype accepts the possibility of a mild reduction in sensitivity but is expected to increase positive predictive value of diagnostic analysis.
Generation of such lists is a critical task that will facilitate the general analysis of clinically relevant variants. The described ongoing effort has cataloged the phenotypic association, inheritance pattern, and strength of evidence for 1620 genes in 25 phenotypic classes (ranging from narrow scope such as hypodontia to broad phenotypic categories such as central-nervous system disorders). The number of variants examined in an analysis depends on the size of the a priori gene list; among over 200 exomes sequenced in NCGENES, for each 100 genes included in a diagnostic list, we have analyzed a median of 5.0 variants previously classified as disease-associated in HGMD, 1.5 rare truncating variants, and 12.9 rare missense variants per individual.
These diagnostic gene lists and the provenance of information used to create them represent an important resource and provide annotations to aid in ongoing adjudication of variants by focusing analysis on the genes with most likely diagnostic relevance in a variety of clinical contexts. Such lists must evolve with burgeoning knowledge; thus the provenance of information and feedback from molecular analysts and clinicians are essential for periodic updates and maintenance of candidate diagnostic gene lists.
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