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

Laura M Amendola, Michael O Dorschner, Peggy D Robertson, Joseph S Salama, Ragan Hart, Brian H Shirts, Mitzi L Murray, Mari J Tokita, Carlos J Gallego, Daniel Seung Kim, James T Bennett, David R Crosslin, Jane Ranchalis, Kelly L Jones, Elisabeth A Rosenthal, Ella R Jarvik, Andy Itsara, Emily H Turner, Daniel S Herman, Jennifer Schleit, Amber Burt, Seema M Jamal, Jenica L Abrudan, Andrew D Johnson, Laura K Conlin, Matthew C Dulik, Avni Santani, Danielle R Metterville, Melissa Kelly, Ann Katherine M Foreman, Kristy Lee, Kent D Taylor, Xiuqing Guo, Kristy Crooks, Lesli A Kiedrowski, Leslie J Raffel, Ora Gordon, Kalotina Machini, Robert J Desnick, Leslie G Biesecker, Steven A Lubitz, Surabhi Mulchandani, Greg M Cooper, Steven Joffe, C Sue Richards, Yaoping Yang, Jerome I Rotter, Stephen S Rich, Christopher J O'Donnell, Jonathan S Berg, Nancy B Spinner, James P Evans, Stephanie M Fullerton, Kathleen A Leppig, Robin L Bennett, Thomas Bird, Virginia P Sybert, William M Grady, Holly K Tabor, Jerry H Kim, Michael J Bamshad, Benjamin Wilfond, Arno G Motulsky, C Ronald Scott, Colin C Pritchard, Tom D Walsh, Wylie Burke, Wendy H Raskind, Peter Byers, Fuki M Hisama, Heidi Rehm, Debbie A Nickerson, Gail P Jarvik, Laura M Amendola, Michael O Dorschner, Peggy D Robertson, Joseph S Salama, Ragan Hart, Brian H Shirts, Mitzi L Murray, Mari J Tokita, Carlos J Gallego, Daniel Seung Kim, James T Bennett, David R Crosslin, Jane Ranchalis, Kelly L Jones, Elisabeth A Rosenthal, Ella R Jarvik, Andy Itsara, Emily H Turner, Daniel S Herman, Jennifer Schleit, Amber Burt, Seema M Jamal, Jenica L Abrudan, Andrew D Johnson, Laura K Conlin, Matthew C Dulik, Avni Santani, Danielle R Metterville, Melissa Kelly, Ann Katherine M Foreman, Kristy Lee, Kent D Taylor, Xiuqing Guo, Kristy Crooks, Lesli A Kiedrowski, Leslie J Raffel, Ora Gordon, Kalotina Machini, Robert J Desnick, Leslie G Biesecker, Steven A Lubitz, Surabhi Mulchandani, Greg M Cooper, Steven Joffe, C Sue Richards, Yaoping Yang, Jerome I Rotter, Stephen S Rich, Christopher J O'Donnell, Jonathan S Berg, Nancy B Spinner, James P Evans, Stephanie M Fullerton, Kathleen A Leppig, Robin L Bennett, Thomas Bird, Virginia P Sybert, William M Grady, Holly K Tabor, Jerry H Kim, Michael J Bamshad, Benjamin Wilfond, Arno G Motulsky, C Ronald Scott, Colin C Pritchard, Tom D Walsh, Wylie Burke, Wendy H Raskind, Peter Byers, Fuki M Hisama, Heidi Rehm, Debbie A Nickerson, Gail P Jarvik

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.

© 2015 Amendola et al.; Published by Cold Spring Harbor Laboratory Press.

Figures

Figure 1.
Figure 1.
Variants reviewed and classifications in actionable ACMG and non-ACMG genes: (P) pathogenic; (LP) likely pathogenic; (VUS) variant of uncertain significance; (LB) likely benign; (EP) expected pathogenic.
Figure 2.
Figure 2.
GERP versus CADD scores of pathogenic, likely pathogenic, and likely benign nondisruptive variants for dominant disorders. Likely benign variants with a GERP score of less than −1.0 are shown with their corresponding CADD scores along the −1 x-axis. Their true coordinates are (GERP, CADD): (−7.77, 0.15), (−7.34, 0.00), (−5.43, 1.93), (−4.01, 11.16), (−2.76, 8.66), (−2.25, 0.66).

References

    1. American College of Medical Genetics and Genomics 2014. ACMG updates recommendation on “opt out” for genome sequencing return of results. .
    1. Berg JS, Amendola LM, Eng C, Van Allen E, Gray SW, Wagle N, Rehm HL, DeChene ET, Dulik MC, Hisama FM, et al. . 2013. Processes and preliminary outputs for identification of actionable genes as incidental findings in genomic sequence data in the Clinical Sequencing Exploratory Research Consortium. Genet Med 15: 860–867.
    1. Biesecker L. 2012. Improving the rigor of mutation reports: biologic parentage and de novo mutations. Hum Mutat 33: 1501–1502.
    1. Brownstein CA, Beggs AH, Homer N, Merriman B, Yu TW, Flannery KC, Dechene ET, Towne MC, Savage SK, Price EN, et al. . 2014. An international effort towards developing standards for best practices in analysis, interpretation and reporting of clinical genome sequencing results in the CLARITY Challenge. Genome Biol 15: R53.
    1. Conti E, Izaurralde E. 2005. Nonsense-mediated mRNA decay: molecular insights and mechanistic variations across species. Curr Opin Cell Biol 17: 316–325.
    1. Cooper GM, Stone EA, Asimenos G, NISC Comparative Sequencing Program, Green ED, Batzoglou S, Sidow A. 2005. Distribution and intensity of constraint in mammalian genomic sequence. Genome Res 15: 901–913.
    1. Davydov EV, Goode DL, Sirota M, Cooper GM, Sidow A, Batzoglou S. 2010. Identifying a high fraction of the human genome to be under selective constraint using GERP++. PLoS Comput Biol 6: e1001025.
    1. Dorschner MO, Amendola LM, Turner EH, Robertson PD, Shirts BH, Gallego CJ, Bennett RL, Jones KL, Tokita MJ, Bennett JT, et al. . 2013. Actionable, pathogenic incidental findings in 1,000 participants’ exomes. Am J Hum Genet 93: 631–640.
    1. Duzkale H, Shen J, McLaughlin H, Alfares A, Kelly MA, Pugh TJ, Funke BH, Rehm HL, Lebo MS. 2013. A systematic approach to assessing the clinical significance of genetic variants. Clin Genet 84: 453–463.
    1. Eggington JM, Bowles KR, Moyes K, Manley S, Esterling L, Sizemore S, Rosenthal E, Theisen A, Saam J, Arnell C, et al. . 2013. A comprehensive laboratory-based program for classification of variants of uncertain significance in hereditary cancer genes. Clin Genet 86: 229–237.
    1. Gonsalves SG, Ng D, Johnston JJ, Teer JK, Stenson PD, Cooper DN, Mullikin JC, Biesecker LG. 2013. Using exome data to identify malignant hyperthermia susceptibility mutations. Anesthesiology 119: 1043–1053.
    1. Green RC, Berg JS, Grody WW, Kalia SS, Korf BR, Martin CL, McGuire AL, Nussbaum RL, O’Daniel JM, Ormond KE, et al. . 2013. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med 15: 565–574.
    1. Hampel H, de la Chapelle A. 2011. The search for unaffected individuals with Lynch syndrome: do the ends justify the means? Cancer Prev Res (Phila) 4: 1–5.
    1. Hartge P, Struewing JP, Wacholder S, Brody LC, Tucker MA. 1999. The prevalence of common BRCA1 and BRCA2 mutations among Ashkenazi Jews. Am J Hum Genet 64: 963–970.
    1. Isidor B, Lindenbaum P, Pichon O, Bézieau S, Dina C, Jacquemont S, Martin-Coignard D, Thauvin-Robinet C, Le Merrer M, Mandel JL, et al. . 2011. Truncating mutations in the last exon of NOTCH2 cause a rare skeletal disorder with osteoporosis. Nat Genet 43: 306–308.
    1. Janavičius R.2010. Founder BRCA1/2 mutations in the Europe: implications for hereditary breast-ovarian cancer prevention and control. EPMA J 1: 397–412.
    1. Johnston JJ, Rubinstein WS, Facio FM, Ng D, Singh LN, Teer JK, Mullikin JC, Biesecker LG. 2012. Secondary variants in individuals undergoing exome sequencing: screening of 572 individuals identifies high-penetrance mutations in cancer-susceptibility genes. Am J Hum Genet 91: 97–108.
    1. Kircher M, Witten DM, Jain P, O’Roak BJ, Cooper GM, Shendure J. 2014. A general framework for estimating the relative pathogenicity of human genetic variants. Nat Genet 46: 310–315.
    1. Lawrence L, Sincan M, Markello T, Adams DR, Gill F, Godfrey R, Golas G, Groden C, Landis D, Nehrebecky M, et al. . 2014. The implications of familial incidental findings from exome sequencing: the NIH Undiagnosed Diseases Program experience. Genet Med 16: 741–750.
    1. MacArthur DG, Manolio TA, Dimmock DP, Rehm HL, Shendure J, Abecasis GR, Adams DR, Altman RB, Antonarakis SE, Ashley EA, et al. . 2014. Guidelines for investigating causality of sequence variants in human disease. Nature 508: 469–476.
    1. Maquat LE. 2004. Nonsense-mediated mRNA decay: splicing, translation and mRNP dynamics. Nat Rev Mol Cell Biol 5: 89–99.
    1. Ng D, Johnston JJ, Teer JK, Singh LN, Peller LC, Wynter JS, Lewis KL, Cooper DN, Stenson PD, Mullikin JC, et al. . 2013. Interpreting secondary cardiac disease variants in an exome cohort. Circ Cardiovasc Genet 6: 337–346.
    1. Patterson N, Price AL, Reich D. 2006. Population structure and eigenanalysis. PLoS Genet 2: e190.
    1. Pirone A, Schredelseker J, Tuluc P, Gravino E, Fortunato G, Flucher BE, Carsana A, Salvatore F, Grabner M. 2010. Identification and functional characterization of malignant hyperthermia mutation T1354S in the outer pore of the Cavα1S-subunit. Am J Physiol Cell Physiol 299: C1345–C1354.
    1. Price AL, Patterson NJ, Plenge RM, Weinblatt ME, Shadick NA, Reich D. 2006. Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 38: 904–909.
    1. Rader DJ, Cohen J, Hobbs HH. 2003. Monogenic hypercholesterolemia: new insights in pathogenesis and treatment. J Clin Invest 111: 1795–1803.
    1. Stenson PD, Mort M, Ball EV, Howells K, Phillips AD, Thomas NS, Cooper DN. 2009. The Human Gene Mutation Database: 2008 update. Genome Med 1: 13.
    1. Thompson BA, Spurdle AB, Plazzer JP, Greenblatt MS, Akagi K, Al-Mulla F, Bapat B, Bernstein I, Capella G, den Dunnen JT, et al. . 2014. Application of a 5-tiered scheme for standardized classification of 2,360 unique mismatch repair gene variants in the InSiGHT locus-specific database. Nat Genet 46: 107–115.

Source: PubMed

스폰서 및 공동 작업자

건강 상태

약물 개입

3
구독하다