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

Pubmed ID: 25637381

Pubmed Central ID: PMC4352885

Journal: Genome research

Publication Date: March 1, 2015

MeSH Terms: Humans, Male, Adult, Female, Gene Frequency, Polymorphism, Single Nucleotide, Phenotype, Genome, Human, Genetic Association Studies, High-Throughput Nucleotide Sequencing, Exome, Genomics, Genetic Testing, Genes, Dominant, Incidental Findings, Black People, White People

Grants: UL1 TR000124, RC2 HL102923, RC2 HL102926, RC2 HL102924, RC2 HL103010, RC2 HL102925, U41HG006834, U01 HG006546, U01 HG006375, U01HG006375, U01HG006487, 5P30CA015704, 1K23HL114724, RC2 HL-102926, P30 CA015704, T32 GM007454, NIH/NIGMS T32 GM007454, UM1HG007301, U41 HG006834, RC2 HL-102923, U01 HG006507, U01HG007307, U01 HG006485, U01HG006500, P30 DK063491, RC2 HL-102924, R01 AG033193, U01HG006485, UM1 HG007292, UM1HG007292, U01 HG006500, RC2 HL-102925, U01HG006546, NHGRI/NCI U01HG006507, U01HG006492, UM1 HG007301, K23 HL114724, RC2 HL-103010, U01 HG007307, U01 HG006487, U01 HG006492, U01 AG049505, R01 CA175716, T32 GM007266

Authors: Guo X, Nickerson DA, Burt A, Kelly M, Lee K, Rosenthal EA, Crosslin DR, Kim DS, Rich SS, Jarvik GP, Amendola LM, Dorschner MO, Robertson PD, Salama JS, Hart R, Shirts BH, Murray ML, Tokita MJ, Gallego CJ, Bennett JT, Ranchalis J, Jones KL, Jarvik ER, Itsara A, Turner EH, Herman DS, Schleit J, Jamal SM, Abrudan JL, Johnson AD, Conlin LK, Dulik MC, Santani A, Metterville DR, Foreman AK, Taylor KD, Crooks K, Kiedrowski LA, Raffel LJ, Gordon O, Machini K, Desnick RJ, Biesecker LG, Lubitz SA, Mulchandani S, Cooper GM, Joffe S, Richards CS, Yang Y, Rotter JI, 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, Scott CR, Pritchard CC, Walsh TD, Burke W, Raskind WH, Byers P, Hisama FM, Rehm H

Cite As: Amendola LM, Dorschner MO, Robertson PD, Salama JS, Hart R, Shirts BH, Murray ML, Tokita MJ, Gallego CJ, Kim DS, 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 AK, 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, Richards CS, 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, Scott CR, Pritchard CC, Walsh TD, Burke W, Raskind WH, Byers P, Hisama FM, Rehm H, Nickerson DA, Jarvik GP. Actionable exomic incidental findings in 6503 participants: challenges of variant classification. Genome Res 2015 Mar;25(3):305-15. Epub 2015 Jan 30.

Studies:

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.