Exome sequencing and genome sequencing have the potential to improve clinical utility for patients undergoing genetic investigations. However, evidence of clinical utility is limited to pediatric populations; we aimed to fill this gap by conducting a systematic review of the literature on the clinical utility of exome/genome sequencing across disease indications in pediatric and adult populations. MEDLINE, EMBASE and Cochrane Library were searched between 2016 and 2020. Quantitative studies evaluating diagnostic yield were included; other measures of clinical utility such as changes to clinical management were documented if reported. Two reviewers screened, extracted data, and appraised risk of bias. Fifty studies met our inclusion criteria. All studies reported diagnostic yield, which ranged from 3 to 70%, with higher range of yields reported for neurological indications and acute illness ranging from 22 to 68% and 37–70%, respectively. Diagnoses triggered a range of clinical management changes including surveillance, reproductive-risk counseling, and identifying at-risk relatives in 4–100% of patients, with higher frequencies reported for acute illness ranging from 67 to 95%. The frequency of variants of uncertain significance ranged from 5 to 85% across studies with a potential trend of decreasing frequency over time and higher rates identified in patients of non-European ancestry. This review provides evidence for a higher range of diagnostic yield of exome/genome sequencing compared to standard genetic tests, particularly in neurological and acute indications. However, we identified significant heterogeneity in study procedures and outcomes, precluding a meaningful meta-analysis and certainty in the evidence available for decision-making. Future research that incorporates a comprehensive and consistent approach in capturing clinical utility of exome/genome sequencing across broader ancestral groups is necessary to improve diagnostic accuracy and yield and allow for analysis of trends over time.
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Aintablian HK, Narayanan V, Belnap N, Ramsey K, Grebe TA (2017) An atypical presentation of ACAD9 deficiency: Diagnosis by whole exome sequencing broadens the phenotypic spectrum and alters treatment approach. Mol Genet Metab Rep 10:38–44. https://doi.org/10.1016/j.ymgmr.2016.12.005
Alankarage D, Ip E, Szot JO, Munro J, Blue GM, Harrison K, Dunwoodie SL (2019) Identification of clinically actionable variants from genome sequencing of families with congenital heart disease. Genet Med 21(5):1111–1120. https://doi.org/10.1038/s41436-018-0296-x
Al-Nabhani M, Al-Rashdi S, Al-Murshedi F, Al-Kindi A, Al-Thihli K, Al-Saegh A, Al-Maawali A (2018) Reanalysis of exome sequencing data of intellectual disability samples: yields and benefits. Clin Genet 94(6):495–501. https://doi.org/10.1111/cge.13438
Alsubaie L, Aloraini T, Amoudi M, Swaid A, Eyiad W, Al Mutairi F, Alfares A (2020) Genomic testing and counseling: the contribution of next-generation sequencing to epilepsy genetics. Ann Hum Genet 84(6):431–436. https://doi.org/10.1111/ahg.12397
Amendola LM, Jarvik GP, Leo MC, McLaughlin HM, Akkari Y, Amaral MD, Rehm HL (2016) Performance of ACMG-AMP variant-interpretation guidelines among nine laboratories in the clinical sequencing exploratory research consortium. Am J Hum Genet 99(1):247. https://doi.org/10.1016/j.ajhg.2016.06.001
American Society of Human Genetics Board of Directors. ASHG Diversity and Inclusion Policy. https://www.ashg.org/about/diversity-inclusion-policy/. Accessed 1 Mar 2021
Arts P, Simons A, AlZahrani MS, Yilmaz E, AlIdrissi E, van Aerde KJ, Hoischen A (2019) Exome sequencing in routine diagnostics: a generic test for 254 patients with primary immunodeficiencies. Genome Med 11(1):38. https://doi.org/10.1186/s13073-019-0649-3
Bergant G, Maver A, Lovrecic L, Čuturilo G, Hodzic A, Peterlin B (2018) Comprehensive use of extended exome analysis improves diagnostic yield in rare disease: a retrospective survey in 1,059 cases. Genet Med 20(3):303–312. https://doi.org/10.1038/gim.2017.142
Bhatia NS, Lim JY, Bonnard C, Kuan JL, Brett M, Wei H, SUREKids Working Group (2020) Singapore undiagnosed disease program: genomic analysis aids diagnosis and clinical management. Arch Dis Child. https://doi.org/10.1136/archdischild-2020-319180
Bombard Y, Clausen M, Mighton C, Carlsson L, Casalino S, Glogowski E, Laupacis A (2018) The Genomics ADvISER: development and usability testing of a decision aid for the selection of incidental sequencing results. Eur J Hum Genet 26(7):984–995. https://doi.org/10.1038/s41431-018-0144-0
Bombard Y, Clausen M, Shickh S, Mighton C, Casalino S, Kim THM, Incidental Genomics Study Team (2020) Effectiveness of the genomics ADvISER decision aid for the selection of secondary findings from genomic sequencing: a randomized clinical trial. Genet Med 22(4):727–735. https://doi.org/10.1038/s41436-019-0702-z
Bossuyt PM, Reitsma JB, Linnet K, Moons KG (2012) Beyond diagnostic accuracy: the clinical utility of diagnostic tests. Clin Chem 58(12):1636–1643. https://doi.org/10.1373/clinchem.2012.182576
Botkin JR, Teutsch SM, Kaye CI, Hayes M, Haddow JE, Bradley LA, EGAPP Working Group (2010) Outcomes of interest in evidence-based evaluations of genetic tests. Genet Med 12(4):228–235. https://doi.org/10.1097/GIM.0b013e3181cdde04
Clark MM, Stark Z, Farnaes L, Tan TY, White SM, Dimmock D, Kingsmore SF (2018) Meta-analysis of the diagnostic and clinical utility of genome and exome sequencing and chromosomal microarray in children with suspected genetic diseases. NPJ Genom Med 3:16. https://doi.org/10.1038/s41525-018-0053-8
Costain G, Cordeiro D, Matviychuk D, Mercimek-Andrews S (2019) Clinical application of targeted next-generation sequencing panels and whole exome sequencing in childhood epilepsy. Neuroscience 418:291–310. https://doi.org/10.1016/j.neuroscience.2019.08.016
Dixon-Woods M, Agarwal S, Jones D, Young B, Sutton A (2005) Synthesising qualitative and quantitative evidence: a review of possible methods. J Health Serv Res Policy 10(1):45–53. https://doi.org/10.1177/135581960501000110
Doyle DL (2009) Genetic service delivery: the current system and its strengths and challenges. Institute of Medicine (US) Roundtable on Translating Genomic-Based Research for Health. In: National Academic Press, Washington (DC). https://www.ncbi.nlm.nih.gov/books/NBK26394/. Accessed 01 Jun 2021
Groopman EE, Marasa M, Cameron-Christie S, Petrovski S, Aggarwal VS, Milo-Rasouly H, Gharavi AG (2019) Diagnostic utility of exome sequencing for kidney disease. N Engl J Med 380(2):142–151. https://doi.org/10.1056/NEJMoa1806891
Haer-Wigman L, van der Schoot V, Feenstra I, Vulto-van Silfhout AT, Gilissen C, Brunner HG, Yntema HG (2019) 1 in 38 individuals at risk of a dominant medically actionable disease. Eur J Hum Genet 27(2):325–330. https://doi.org/10.1038/s41431-018-0284-2
Harrison SM, Dolinsky JS, Knight Johnson AE, Pesaran T, Azzariti DR, Bale S, Rehm HL (2017) Clinical laboratories collaborate to resolve differences in variant interpretations submitted to ClinVar. Genet Med 19(10):1096–1104. https://doi.org/10.1038/gim.2017.14
Hayeems RZ, Dimmock D, Bick D, Belmont JW, Green RC, Lanpher B, Medical Genome Initiative (2020) Clinical utility of genomic sequencing: a measurement toolkit. NPJ Genom Med 5(1):56. https://doi.org/10.1038/s41525-020-00164-7
Helbig KL, Farwell Hagman KD, Shinde DN, Mroske C, Powis Z, Li S, Helbig I (2016) Diagnostic exome sequencing provides a molecular diagnosis for a significant proportion of patients with epilepsy. Genet Med 18(9):898–905. https://doi.org/10.1038/gim.2015.186
Hu X, Li N, Xu Y, Li G, Yu T, Yao RE, Shen Y (2018) Proband-only medical exome sequencing as a cost-effective first-tier genetic diagnostic test for patients without prior molecular tests and clinical diagnosis in a developing country: the China experience. Genet Med 20(9):1045–1053. https://doi.org/10.1038/gim.2017.195
Ji J, Shen L, Bootwalla M, Quindipan C, Tatarinova T, Maglinte DT, Gai X (2019) A semiautomated whole-exome sequencing workflow leads to increased diagnostic yield and identification of novel candidate variants. Cold Spring Harb Mol Case Stud. https://doi.org/10.1101/mcs.a003756
Kalia SS, Adelman K, Bale SJ, Chung WK, Eng C, Evans JP, Miller DT (2017) Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics. Genet Med 19(2):249–255. https://doi.org/10.1038/gim.2016.190
Lazaridis KN, Schahl KA, Cousin MA, Babovic-Vuksanovic D, Riegert-Johnson DL, Gavrilova RH, Individualized Medicine Clinic Members (2016) Outcome of whole exome sequencing for diagnostic odyssey cases of an individualized medicine clinic: the Mayo Clinic experience. Mayo Clin Proc 91(3):297–307. https://doi.org/10.1016/j.mayocp.2015.12.018
Lee H, Deignan JL, Dorrani N, Strom SP, Kantarci S, Quintero-Rivera F, Nelson SF (2014) Clinical exome sequencing for genetic identification of rare Mendelian disorders. JAMA 312(18):1880–1887. https://doi.org/10.1001/jama.2014.14604
Leeflang MM, Deeks JJ, Gatsonis C, Bossuyt PM (2008) Cochrane Diagnostic Test Accuracy Working Group. Systematic reviews of diagnostic test accuracy. Ann Intern Med 149(12):889–897. https://doi.org/10.7326/0003-4819-149-12-200812160-00008
Lionel AC, Costain G, Monfared N, Walker S, Reuter MS, Hosseini SM, Marshall CR (2017) Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test. Genet Med. https://doi.org/10.1038/gim.2017.119
Manrai AK, Funke BH, Rehm HL, Olesen MS, Maron BA, Szolovits P, Kohane IS (2016) Genetic misdiagnoses and the potential for health disparities. N Engl J Med 375(7):655–665. https://doi.org/10.1056/NEJMsa1507092
Marchuk DS, Crooks K, Strande N, Kaiser-Rogers K, Milko LV, Brandt A, Berg JS (2018) Increasing the diagnostic yield of exome sequencing by copy number variant analysis. PLoS One 13(12):e0209185. https://doi.org/10.1371/journal.pone.0209185
Marelli C, Guissart C, Hubsch C, Renaud M, Villemin JP, Larrieu L, Koenig M (2016) Mini-exome coupled to read-depth based copy number variation analysis in patients with inherited ataxias. Hum Mutat 37(12):1340–1353. https://doi.org/10.1002/humu.23063
Miller NA, Farrow EG, Gibson M, Willig LK, Twist G, Yoo B, Kingsmore SF (2015) A 26-h system of highly sensitive whole genome sequencing for emergency management of genetic diseases. Genome Med 7:100. https://doi.org/10.1186/s13073-015-0221-8
Moher D, Liberati A, Tetzlaff J, Altman DG, PRISMA-Group (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Ann Intern Med 151(4):264–269
Monies D, Abouelhoda M, Assoum M, Moghrabi N, Rafiullah R, Almontashiri N, Alkuraya FS (2019) Lessons learned from large-scale, first-tier clinical exome sequencing in a highly consanguineous population. Am J Hum Genet 105(4):879. https://doi.org/10.1016/j.ajhg.2019.09.019
Mueller M, D’Addario M, Egger M, Cevallos M, Dekkers O, Mugglin C, Scott P (2018) Methods to systematically review and meta-analyse observational studies: a systematic scoping review of recommendations. BMC Med Res Methodol 18(1):44. https://doi.org/10.1186/s12874-018-0495-9
Nykamp K, Anderson M, Powers M, Garcia J, Herrera B, Ho YY, The Invitae Clinical Genomics Group (2017) Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. Genet Med 19(10):1105–1117. https://doi.org/10.1038/gim.2017.37
Peterson RE, Kuchenbaecker K, Walters RK, Chen CY, Popejoy AB, Periyasamy S, Duncan LE (2019) Genome-wide association studies in ancestrally diverse populations: opportunities, methods, pitfalls, and recommendations. Cell 179(3):589–603. https://doi.org/10.1016/j.cell.2019.08.051
Petrikin JE, Willig LK, Smith LD, Kingsmore SF (2015) Rapid whole genome sequencing and precision neonatology. Semin Perinatol 39(8):623–631. https://doi.org/10.1053/j.semperi.2015.09.009
Pfundt R, Del Rosario M, Vissers LELM, Kwint MP, Janssen IM, de Leeuw N, Hehir-Kwa JY (2017) Detection of clinically relevant copy-number variants by exome sequencing in a large cohort of genetic disorders. Genet Med 19(6):667–675. https://doi.org/10.1038/gim.2016.163
Popejoy AB, Fullerton SM (2016) Genomics is failing on diversity. Nature 538(7624):161–164. https://doi.org/10.1038/538161a
Powis Z, Espenschied CR, LaDuca H, Hagman KD, Paudyal T, Li S, Tang S (2018) Clinical germline diagnostic exome sequencing for hereditary cancer: findings within novel candidate genes are prevalent. Cancer Genet 224–225:12–20. https://doi.org/10.1016/j.cancergen.2018.04.002
Powis Z, Towne MC, Hagman KDF, Blanco K, Palmaer E, Castro A, Sidiropoulos C (2020) Clinical diagnostic exome sequencing in dystonia: genetic testing challenges for complex conditions. Clin Genet 97(2):305–311. https://doi.org/10.1111/cge.13657
Retterer K, Juusola J, Cho MT, Vitazka P, Millan F, Gibellini F, Bale S (2016) Clinical application of whole-exome sequencing across clinical indications. Genet Med 18(7):696–704. https://doi.org/10.1038/gim.2015.148
Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, ACMG Laboratory Quality Assurance Committee (2015) Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med 17(5):405–424. https://doi.org/10.1038/gim.2015.30
Rossi M, El-Khechen D, Black MH, Farwell Hagman KD, Tang S, Powis Z (2017) Outcomes of diagnostic exome sequencing in patients with diagnosed or suspected autism spectrum disorders. Pediatr Neurol 70:34-43.e32. https://doi.org/10.1016/j.pediatrneurol.2017.01.033
Salfati EL, Spencer EG, Topol SE, Muse ED, Rueda M, Lucas JR, Torkamani A (2019) Re-analysis of whole-exome sequencing data uncovers novel diagnostic variants and improves molecular diagnostic yields for sudden death and idiopathic diseases. Genome Med 11(1):83. https://doi.org/10.1186/s13073-019-0702-2
Saunders CJ, Miller NA, Soden SE, Dinwiddie DL, Noll A, Alnadi NA, Kingsmore SF (2012) Rapid whole-genome sequencing for genetic disease diagnosis in neonatal intensive care units. Sci Transl Med 4(154):154ra135. https://doi.org/10.1126/scitranslmed.3004041
Schmitz-Abe K, Li Q, Rosen SM, Nori N, Madden JA, Genetti CA, Agrawal PB (2019) Unique bioinformatic approach and comprehensive reanalysis improve diagnostic yield of clinical exomes. Eur J Hum Genet 27(9):1398–1405. https://doi.org/10.1038/s41431-019-0401-x
Schwarze K, Buchanan J, Taylor JC, Wordsworth S (2018) Are whole-exome and whole-genome sequencing approaches cost-effective? A systematic review of the literature. Genet Med 20:1122–1130. https://doi.org/10.1038/gim.2017.247
Scocchia A, Wigby KM, Masser-Frye D, Del Campo M, Galarreta CI, Thorpe E, Taft RJ (2019) Clinical whole genome sequencing as a first-tier test at a resource-limited dysmorphology clinic in Mexico. NPJ Genom Med 4:5. https://doi.org/10.1038/s41525-018-0076-1
Seidelmann SB, Smith E, Subrahmanyan L, Dykas D, Abou Ziki MD, Azari B, Mani A (2017) Application of whole exome sequencing in the clinical diagnosis and management of inherited cardiovascular diseases in adults. Circ Cardiovasc Genet. https://doi.org/10.1161/CIRCGENETICS.116.001573
Shickh S, Clausen M, Mighton C, Casalino S, Joshi E, Glogowski E, Bombard Y (2018) Evaluation of a decision aid for incidental genomic results, the Genomics ADvISER: protocol for a mixed methods randomised controlled trial. BMJ Open 8(4):e021876. https://doi.org/10.1136/bmjopen-2018-021876
Shickh S, Rafferty SA, Clausen M, Kodida R, Mighton C, Panchal S (2021) The role of digital tools in the delivery of genomic medicine: enhancing patient-centered care. Genet Med. https://doi.org/10.1038/s41436-021-01112-1
Smith HS, Swint JM, Lalani SR, Yamal JM, de Oliveira Otto MC, Castellanos S, Russell HV (2019) Clinical application of genome and exome sequencing as a diagnostic tool for pediatric patients: a scoping review of the literature. Genet Med 21(1):3–16. https://doi.org/10.1038/s41436-018-0024-6
Stark Z, Tan TY, Chong B, Brett GR, Yap P, Walsh M, White SM (2016) A prospective evaluation of whole-exome sequencing as a first-tier molecular test in infants with suspected monogenic disorders. Genet Med 18(11):1090–1096. https://doi.org/10.1038/gim.2016.1
Stark Z, Schofield D, Martyn M, Rynehart L, Shrestha R, Alam K, White SM (2019) Does genomic sequencing early in the diagnostic trajectory make a difference? A follow-up study of clinical outcomes and cost-effectiveness. Genet Med 21(1):173–180. https://doi.org/10.1038/s41436-018-0006-8
Stavropoulos DJ, Merico D, Jobling R, Bowdin S, Monfared N, Thiruvahindrapuram B, Marshall CR (2016) Whole genome sequencing expands diagnostic utility and improves clinical management in pediatric medicine. NPJ Genom Med. https://doi.org/10.1038/npjgenmed.2015.12
Stojanovic JR, Miletic A, Peterlin B, Maver A, Mijovic M, Borlja N, Cuturilo G (2020) Diagnostic and clinical utility of clinical exome sequencing in children with moderate and severe global developmental delay/intellectual disability. J Child Neurol 35(2):116–131. https://doi.org/10.1177/0883073819879835
Sturm A (2019) Improving Access to Genetic Counselors under H.R. 3235, the “Access to Genetic Counselor Services Act” of 2019. American Society of Human Genetics. https://www.ashg.org/publications-news/ashg-news/nsgc-hr-3235/. Accessed 1 Jun 2021
Tan TY, Dillon OJ, Stark Z, Schofield D, Alam K, Shrestha R, White SM (2017) Diagnostic impact and cost-effectiveness of whole-exome sequencing for ambulant children with suspected monogenic conditions. JAMA Pediatr 171(9):855–862. https://doi.org/10.1001/jamapediatrics.2017.1755
Tarailo-Graovac M, Shyr C, Ross CJ, Horvath GA, Salvarinova R, Ye XC, van Karnebeek CD (2016) Exome sequencing and the management of neurometabolic disorders. N Engl J Med 374(23):2246–2255. https://doi.org/10.1056/NEJMoa1515792
Teutsch SM, Bradley LA, Palomaki GE, Haddow JE, Piper M, Calonge N, EGAPP Working Group (2009) The evaluation of genomic applications in practice and prevention (EGAPP) initiative: methods of the EGAPP Working Group. Genet Med 11(1):3–14. https://doi.org/10.1097/GIM.0b013e318184137c
Trujillano D, Bertoli-Avella AM, Kumar Kandaswamy K, Weiss ME, Köster J, Marais A, Abou Jamra R (2017) Clinical exome sequencing: results from 2819 samples reflecting 1000 families. Eur J Hum Genet 25(2):176–182. https://doi.org/10.1038/ejhg.2016.146
Tsuchida N, Nakashima M, Kato M, Heyman E, Inui T, Haginoya K, Matsumoto N (2018) Detection of copy number variations in epilepsy using exome data. Clin Genet 93(3):577–587. https://doi.org/10.1111/cge.13144
Villegas C, Haga SB (2019) Access to genetic counselors in the Southern United States. J Pers Med. https://doi.org/10.3390/jpm9030033
Walsh M, Bell KM, Chong B, Creed E, Brett GR, Pope K, Melbourne Genomics Health Alliance (2017) Diagnostic and cost utility of whole exome sequencing in peripheral neuropathy. Ann Clin Transl Neurol 4(5):318–325. https://doi.org/10.1002/acn3.409
Wang H, Qian Y, Lu Y, Qin Q, Lu G, Cheng G, Zhou W (2020) Clinical utility of 24-h rapid trio-exome sequencing for critically ill infants. NPJ Genom Med 5:20. https://doi.org/10.1038/s41525-020-0129-0
We would like to thank Mark Dobrow and Lusine Abrahamyan for their feedback on the research question and the first version of the manuscript and Agnes Sebastian for her assistance retrieving articles for the full text review.
SS received support from the Canadian Institutes of Health Research (CIHR, GSD-425969) and the Research Training Centre at St. Michael’s Hospital. CM received support from the Research Training Centre at St. Michael’s Hospital, a doctoral award from the Canadian Institutes of Health Research (CIHR, GSD-164222) and a studentship funded by the Canadian Centre for Applied Research in Cancer Control (ARCC); ARCC receives core funding from the Canadian Cancer Society (Grant #2015-703549). YB was supported by a CIHR New Investigator Award. Funding agencies did not play any role in design of the study, data collection, analysis, and interpretation of data.
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Shickh, S., Mighton, C., Uleryk, E. et al. The clinical utility of exome and genome sequencing across clinical indications: a systematic review. Hum Genet 140, 1403–1416 (2021). https://doi.org/10.1007/s00439-021-02331-x