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Actionable exomic incidental findings in 6503 participants: challenges of variant classification.

TitleActionable exomic incidental findings in 6503 participants: challenges of variant classification.
Publication TypeJournal Article
Year of Publication2015
AuthorsAmendola LM, Dorschner MO, Robertson PD, Salama JS, Hart R, Shirts BH, Murray ML, Tokita MJ, Gallego CJ, Kim DSeung, Bennett JT, Crosslin DR, Ranchalis J, Jones KL, Rosenthal EA, Jarvik ER, Itsara A, Turner EH, Herman DS, Schleit J, Burt A, Jamal SM, Abrudan JL, Johnson AD, Conlin LK, Dulik MC, Santani A, Metterville DR, Kelly M, Foreman AKatherine, Lee K, Taylor KD, Guo X, Crooks K, Kiedrowski LA, Raffel LJ, Gordon O, Machini K, Desnick RJ, Biesecker LG, Lubitz SA, Mulchandani S, Cooper GM, Joffe S, C Richards S, Yang Y, Rotter JI, Rich SS, O'Donnell CJ, Berg JS, Spinner NB, Evans JP, Fullerton SM, Leppig KA, Bennett RL, Bird T, Sybert VP, Grady WM, Tabor HK, Kim JH, Bamshad MJ, Wilfond B, Motulsky AG, C Scott R, Pritchard CC, Walsh TD, Burke W, Raskind WH, Byers P, Hisama FM, Rehm H, Nickerson DA
Secondary AuthorsJarvik GP
JournalGenome Res
Volume25
Issue3
Pagination305-15
Date Published2015 Mar
ISSN1549-5469
KeywordsAdult, African Continental Ancestry Group, European Continental Ancestry Group, Exome, Female, Gene Frequency, Genes, Dominant, Genetic Association Studies, Genetic Testing, Genome, Human, Genomics, High-Throughput Nucleotide Sequencing, Humans, Incidental Findings, Male, Phenotype, Polymorphism, Single Nucleotide
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.

DOI10.1101/gr.183483.114
Alternate JournalGenome Res
PubMed ID25637381
PubMed Central IDPMC4352885
Grant ListU41HG006834 / HG / NHGRI NIH HHS / United States
U01 HG006546 / HG / NHGRI NIH HHS / United States
RC2 HL102923 / HL / NHLBI NIH HHS / United States
U01 HG006375 / HG / NHGRI NIH HHS / United States
U01HG006375 / HG / NHGRI NIH HHS / United States
U01HG006487 / HG / NHGRI NIH HHS / United States
5P30CA015704 / CA / NCI NIH HHS / United States
RC2 HL102926 / HL / NHLBI NIH HHS / United States
1K23HL114724 / HL / NHLBI NIH HHS / United States
RC2 HL-102926 / HL / NHLBI NIH HHS / United States
P30 CA015704 / CA / NCI NIH HHS / United States
T32 GM007454 / GM / NIGMS NIH HHS / United States
R01 CA175716 / CA / NCI NIH HHS / United States
NIH/NIGMS T32 GM007454 / / PHS HHS / United States
UM1HG007301 / HG / NHGRI NIH HHS / United States
U41 HG006834 / HG / NHGRI NIH HHS / United States
RC2 HL-102923 / HL / NHLBI NIH HHS / United States
U01 HG006507 / HG / NHGRI NIH HHS / United States
UL1 TR000124 / TR / NCATS NIH HHS / United States
U01HG007307 / HG / NHGRI NIH HHS / United States
U01 HG006485 / HG / NHGRI NIH HHS / United States
U01HG006500 / HG / NHGRI NIH HHS / United States
P30 DK063491 / DK / NIDDK NIH HHS / United States
RC2 HL-102924 / HL / NHLBI NIH HHS / United States
RC2 HL102924 / HL / NHLBI NIH HHS / United States
R01 AG033193 / AG / NIA NIH HHS / United States
U01HG006485 / HG / NHGRI NIH HHS / United States
UM1 HG007292 / HG / NHGRI NIH HHS / United States
UM1HG007292 / HG / NHGRI NIH HHS / United States
U01 HG006500 / HG / NHGRI NIH HHS / United States
RC2 HL-102925 / HL / NHLBI NIH HHS / United States
RC2 HL103010 / HL / NHLBI NIH HHS / United States
U01HG006546 / HG / NHGRI NIH HHS / United States
T32 GM007266 / GM / NIGMS NIH HHS / United States
NHGRI/NCI U01HG006507 / / PHS HHS / United States
U01HG006492 / HG / NHGRI NIH HHS / United States
UM1 HG007301 / HG / NHGRI NIH HHS / United States
K23 HL114724 / HL / NHLBI NIH HHS / United States
RC2 HL-103010 / HL / NHLBI NIH HHS / United States
RC2 HL102925 / HL / NHLBI NIH HHS / United States
U01 HG007307 / HG / NHGRI NIH HHS / United States
U01 HG006487 / HG / NHGRI NIH HHS / United States
U01 HG006492 / HG / NHGRI NIH HHS / United States
U01 AG049505 / AG / NIA NIH HHS / United States