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

被引：277

作者：

Amendola, Laura M. ^{[1
]}

Dorschner, Michael O. ^{[2
,3
,4
]}

Robertson, Peggy D. ^{[2
]}

Salama, Joseph S. ^{[1
]}

Hart, Ragan ^{[1
]}

Shirts, Brian H. ^{[3
]}

Murray, Mitzi L. ^{[1
,5
]}

Tokita, Mari J. ^{[1
]}

Gallego, Carlos J. ^{[1
]}

Kim, Daniel Seung ^{[2
]}

Bennett, James T. ^{[1
,6
]}

Crosslin, David R. ^{[1
,2
]}

Ranchalis, Jane ^{[1
]}

Jones, Kelly L. ^{[6
]}

Rosenthal, Elisabeth A. ^{[1
]}

Jarvik, Ella R. ^{[1
]}

Itsara, Andy ^{[1
]}

Turner, Emily H. ^{[2
,3
]}

Herman, Daniel S. ^{[3
]}

Schleit, Jennifer ^{[5
]}

Burt, Amber ^{[1
]}

Jamal, Seema M. ^{[7
]}

Abrudan, Jenica L. ^{[8
,9
]}

Johnson, Andrew D. ^{[10
]}

Conlin, Laura K. ^{[9
,11
]}

Dulik, Matthew C. ^{[9
,12
]}

Santani, Avni ^{[9
,11
]}

Metterville, Danielle R. ^{[13
]}

Kelly, Melissa ^{[14
]}

Foreman, Ann Katherine M. ^{[15
]}

Lee, Kristy

Taylor, Kent D. ^{[16
,17
]}

Guo, Xiuqing ^{[16
,17
]}

Crooks, Kristy ^{[18
]}

Kiedrowski, Lesli A. ^{[19
]}

Raffe, Leslie J. ^{[20
]}

Gordon, Ora ^{[20
]}

Machini, Kalotina ^{[21
,22
]}

Desnick, Robe ^{[23
]}

Biesecker, Leslie G. ^{[24
]}

Lubitz, Steven A. ^{[25
,26
]}

Mulchandani, Surabhi

Cooper, Greg M. ^{[27
]}

Joffe, Steven ^{[28
]}

Richards, C. Sue ^{[29
]}

Yang, Yaoping ^{[30
,32
,33
]}

Rotter, Jerome I. ^{[16
,17
]}

Rich, Stephen S. ^{[31
,34
]}

O'Donne, Christopher J. ^{[10
,35
]}

Berg, Jonathan S.

机构：

[1] Univ Washington, Dept Med, Div Med Genet, Seattle, WA 98195 USA

[2] Univ Washington, Dept Genome Sci, Seattle, WA 98195 USA

[3] Univ Washington, Dept Lab Med, Seattle, WA 98195 USA

[4] Univ Washington, Dept Psychiat & Behav Sci, Seattle, WA 98195 USA

[5] Univ Washington, Dept Pathol, Seattle, WA 98195 USA

[6] Univ Washington, Dept Pediat, Seattle, WA 98195 USA

[7] Univ Washington, Dept Pediat, Div Med Genet, Seattle, WA 98195 USA

[8] Childrens Hosp Philadelphia, Dept Genet, Philadelphia, PA 19104 USA

[9] Childrens Hosp Philadelphia, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA

[10] NHLBI, Framingham Heart Study, Div Intramural Res, Framingham, MA 01702 USA

[11] Univ Penn, Dept Pathol & Lab Med, Philadelphia, PA 19104 USA

[12] Childrens Hosp Philadelphia, Dept Pediat, Div Human Genet, Philadelphia, PA 19104 USA

[13] Partners Healthcare, Mol Med Lab, Boston, MA 02115 USA

[14] Partners Healthcare Personalized Med, Boston, MA 02115 USA

[15] Univ N Carolina, Dept Genet, Chapel Hill, NC 27599 USA

[16] Harbor UCLA, Los Angeles Biomed Res Inst, Translat Genom & Populat Sci, Torrance, CA 90502 USA

[17] Harbor UCLA, Dept Pediat, Torrance, CA 90502 USA

[18] Univ N Carolina, Dept Pathol & Lab Med, Chapel Hill, NC 27514 USA

[19] Univ Texas SW Med Ctr Dallas, Dept Canc Genet, Dallas, TX 75390 USA

[20] Cedars Sinai Med Ctr, Med Genet Res Inst, Los Angeles, CA 90048 USA

[21] Brigham & Womens Hosp, Dept Pathol, Boston, MA 02115 USA

[22] Harvard Univ, Sch Med, Dept Pathol, Boston, MA 02115 USA

[23] Mt Sinai Hosp, Dept Genet & Genom Med, Div Med Genet, New York, NY 10029 USA

[24] NHGRI, Genet Dis Res Branch, Bethesda, MD 20892 USA

[25] Massachusetts Gen Hosp, Cardiac Arrhythmia Serv, Boston, MA 02114 USA

[26] Massachusetts Gen Hosp, Cardiovasc Res Ctr, Boston, MA 02114 USA

[27] HudsonAlpha Inst Biotechnol Huntsville, Huntsville, AL 35806 USA

[28] Univ Penn, Perelman Sch Med, Dept Med Eth & Hlth Policy, Philadelphia, PA 19104 USA

[29] Oregon Hlth & Sci Univ, Dept Mol & Med Genet, Portland, OR 97239 USA

[30] Harbor UCLA, Dept Pediat, Div Infect Dis, Torrance, CA 90502 USA

[31] Harbor UCLA, Dept Pediat, Div Infect Dis, Torrance, CA 90502 USA

[32] Harbor UCLA, Los Angeles Biomed Res Inst, Torrance, CA 90502 USA

[33] Harbor UCLA, Dept Pediat, Torrance, CA 90502 USA

[34] Univ Virginia, Ctr Publ Hlth Genom, Charlottesville, VA 22908 USA

[35] Massachusetts Gen Hosp, Div Cardiol, Boston, MA 02114 USA

[36] Massachusetts Gen Hosp, Dept Bioeth & Humanities, Seattle, WA 98195 USA

[37] Grp Hlth Cooperat Puget Sound, Genet Serv, Seattle, WA 98112 USA

[38] Univ Washington, Dept Neurol, Seattle, WA 98195 USA

[39] Vet Affairs Puget Sound Hlth Care Syst Geriatr Re, Seattle, WA 98108 USA

[40] Grp Hlth Cooperat Puget Sound, Dermatol, Seattle, WA 98112 USA

[41] Fred Hutchinson Canc Res Ctr, Div Clin Res, Seattle, WA 98109 USA

[42] Univ Washington, Dept Med, Div Gastroenterol, Seattle, WA 98195 USA

[43] Seattle Childrens Res Inst, Treuman Katz Ctr Pediat Bioeth, Washington, DC 98105 USA

[44] Univ Washington, Dept Anesthesiol & Pain Med, Seattle, WA 98195 USA

[45] Univ Washington, Dept Pediat, Div Bioeth, Seattle, WA 98195 USA

来源：

GENOME RESEARCH | 2015年 / 25卷 / 03期

关键词：

MESSENGER-RNA DECAY; MUTATIONS; IDENTIFICATION; INDIVIDUALS; INSIGHTS;

D O I：

10.1101/gr.183483.114

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：305 / 315

页数：11

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