Advertisement

Human Genetics

, Volume 135, Issue 6, pp 643–654 | Cite as

A Clinician’s perspective on clinical exome sequencing

  • Anne H. O’Donnell-Luria
  • David T. Miller
Review
Part of the following topical collections:
  1. Exome Sequencing

Abstract

Clinical exome sequencing has clearly improved our ability as clinicians to identify the cause of a wide variety of disorders. Prior to exome sequencing, a majority of patients with apparent syndromes never received a specific molecular genetic diagnosis despite extensive diagnostic odysseys. Even for those receiving an answer to the question of what caused their disorder, the diagnostic odyssey often spanned years to decades. Determining the particular genetic cause in an individual patient can be challenging due to inherent phenotypic and genetic heterogeneity of disease, technical limitations of testing or both. Blended phenotypes, due to multiple monogenic disorders in the same patient, are true dilemmas for traditional genetic evaluations, but are increasingly being diagnosed through clinical exome sequencing. New sequencing technologies have increased the proportion of patients receiving molecular diagnoses, while significantly shortening the time scale, providing multiple benefits for the health-care team, patient and family.

Keywords

Whole Genome Sequencing Exome Sequencing Genetic Diagnosis Pathogenic Variant Gene Panel 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgments

DTM receives partial funding through grant NHGRI U41 HG006834 “ClinGen: a Clinical Genomics Database,” and is a part-time clinical consultant for Claritas Genomics through a non-equity professional services agreement. AHOL is supported by the Pfizer/ACMGF Clinical Genetics Fellowship for Translational Genomic Scholars.

References

  1. ACMG Board of Directors (2012) Points to consider in the clinical application of genomic sequencing. Genet Med Off J Am Coll Med Genet 14:759–761. doi: 10.1038/gim.2012.74 Google Scholar
  2. ACMG Board of Directors (2013) Points to consider for informed consent for genome/exome sequencing. Genet Med Off J Am Coll Med Genet 15:748–749. doi: 10.1038/gim.2013.94 Google Scholar
  3. Alamillo CL, Powis Z, Farwell K et al (2015) Exome sequencing positively identified relevant alterations in more than half of cases with an indication of prenatal ultrasound anomalies. Prenat Diagn 35:1073–1078. doi: 10.1002/pd.4648 CrossRefPubMedGoogle Scholar
  4. Amberger JS, Bocchini CA, Schiettecatte F et al (2015) OMIM.org: online Mendelian Inheritance in Man (OMIM®), an online catalog of human genes and genetic disorders. Nucl Acids Res 43:D789–D798. doi: 10.1093/nar/gku1205 CrossRefPubMedPubMedCentralGoogle Scholar
  5. Amendola LM, Dorschner MO, Robertson PD et al (2015) Actionable exomic incidental findings in 6503 participants: challenges of variant classification. Genome Res 25:305–315. doi: 10.1101/gr.183483.114 CrossRefPubMedPubMedCentralGoogle Scholar
  6. Amor D, Rose C, White S, et al (2016) POSSUMweb. http://www.possum.net.au. Accessed 25 Jan 2016
  7. Bell CJ, Dinwiddie DL, Miller NA et al (2011) Carrier testing for severe childhood recessive diseases by next-generation sequencing. Sci Transl Med 3:65ra4. doi: 10.1126/scitranslmed.3001756 CrossRefPubMedPubMedCentralGoogle Scholar
  8. Bernhardt BA, Roche MI, Perry DL et al (2015) Experiences with obtaining informed consent for genomic sequencing. Am J Med Genet A 167A:2635–2646. doi: 10.1002/ajmg.a.37256 CrossRefPubMedGoogle Scholar
  9. Buske OJ, Girdea M, Dumitriu S et al (2015) PhenomeCentral: a portal for phenotypic and genotypic matchmaking of patients with rare genetic diseases. Hum Mutat 36:931–940. doi: 10.1002/humu.22851 CrossRefPubMedGoogle Scholar
  10. Carss KJ, Hillman SC, Parthiban V et al (2014) Exome sequencing improves genetic diagnosis of structural fetal abnormalities revealed by ultrasound. Hum Mol Genet 23:3269–3277. doi: 10.1093/hmg/ddu038 CrossRefPubMedPubMedCentralGoogle Scholar
  11. Chong JX, Buckingham KJ, Jhangiani SN et al (2015) The genetic basis of mendelian phenotypes: discoveries, challenges, and opportunities. Am J Hum Genet 97:199–215. doi: 10.1016/j.ajhg.2015.06.009 CrossRefPubMedPubMedCentralGoogle Scholar
  12. de Ligt J, Willemsen MH, van Bon BWM et al (2012) Diagnostic exome sequencing in persons with severe intellectual disability. N Engl J Med 367:1921–1929. doi: 10.1056/NEJMoa1206524 CrossRefPubMedGoogle Scholar
  13. Dorschner MO, Amendola LM, Turner EH et al (2013) Actionable, pathogenic incidental findings in 1,000 participants’ exomes. Am J Hum Genet 93:631–640. doi: 10.1016/j.ajhg.2013.08.006 CrossRefPubMedPubMedCentralGoogle Scholar
  14. Drury S, Williams H, Trump N et al (2015) Exome sequencing for prenatal diagnosis of fetuses with sonographic abnormalities. Prenat Diagn 35:1010–1017. doi: 10.1002/pd.4675 CrossRefPubMedGoogle Scholar
  15. Farwell KD, Shahmirzadi L, El-Khechen D et al (2015) Enhanced utility of family-centered diagnostic exome sequencing with inheritance model-based analysis: results from 500 unselected families with undiagnosed genetic conditions. Genet Med Off J Am Coll Med Genet 17:578–586. doi: 10.1038/gim.2014.154 Google Scholar
  16. Fernandez BA, Green JS, Bursey F et al (2012) Adult siblings with homozygous G6PC3 mutations expand our understanding of the severe congenital neutropenia type 4 (SCN4) phenotype. BMC Med Genet 13:111. doi: 10.1186/1471-2350-13-111 CrossRefPubMedPubMedCentralGoogle Scholar
  17. Fogel BL, Lee H, Deignan JL et al (2014) Exome sequencing in the clinical diagnosis of sporadic or familial cerebellar ataxia. JAMA Neurol 71:1237–1246. doi: 10.1001/jamaneurol.2014.1944 CrossRefPubMedPubMedCentralGoogle Scholar
  18. Fokkema IFAC, Taschner PEM, Schaafsma GCP et al (2011) LOVD v. 2.0: the next generation in gene variant databases. Hum Mutat 32:557–563. doi: 10.1002/humu.21438 CrossRefPubMedGoogle Scholar
  19. Fryns J-P, de Ravel TJL (2002) London Dysmorphology Database, London Neurogenetics Database and Dysmorphology Photo Library on CD-ROM [Version 3] 2001R. M. Winter, M. Baraitser, Oxford University Press, ISBN 019851-780, pound sterling 1595. Hum Genet 111:113. doi: 10.1007/s00439-002-0759-6 CrossRefPubMedGoogle Scholar
  20. Genetic and Rare Diseases (GARD) Information Center: Natl. Inst. Health Off. Rare Dis. https://rarediseases.info.nih.gov/. Accessed 30 Dec 2015
  21. Gilissen C, Hehir-Kwa JY, Thung DT et al (2014) Genome sequencing identifies major causes of severe intellectual disability. Nature 511:344–347. doi: 10.1038/nature13394 CrossRefPubMedGoogle Scholar
  22. Goodwin G, Hawley PP, Miller DT (2016) A case of HDR syndrome and Ichthyosis: dual diagnosis by whole genome sequencing of novel mutations in GATA3 and STS genes. J Clin Endocrinol Metab 101:837–840. doi: 10.1210/jc.2015-3704 CrossRefPubMedGoogle Scholar
  23. Graungaard AH, Skov L (2007) Why do we need a diagnosis? A qualitative study of parents’ experiences, coping and needs, when the newborn child is severely disabled. Child Care Health Dev 33:296–307. doi: 10.1111/j.1365-2214.2006.00666.x CrossRefPubMedGoogle Scholar
  24. Green RC, Berg JS, Grody WW et al (2013) ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med Off J Am Coll Med Genet 15:565–574. doi: 10.1038/gim.2013.73 Google Scholar
  25. Green RC, Lautenbach D, McGuire AL (2015) GINA, genetic discrimination, and genomic medicine. N Engl J Med 372:397–399. doi: 10.1056/NEJMp1404776 CrossRefPubMedGoogle Scholar
  26. Gripp KW, Slavotinek AM, Hall JG, Allanson JE (2013) Handbook of physical measurements, 3rd edn. Oxford University Press, Oxford, UKGoogle Scholar
  27. Groza T, Köhler S, Moldenhauer D et al (2015) The Human phenotype ontology: semantic unification of common and rare disease. Am J Hum Genet 97:111–124. doi: 10.1016/j.ajhg.2015.05.020 CrossRefPubMedPubMedCentralGoogle Scholar
  28. Iglesias A, Anyane-Yeboa K, Wynn J et al (2014) The usefulness of whole-exome sequencing in routine clinical practice. Genet Med Off J Am Coll Med Genet 16:922–931. doi: 10.1038/gim.2014.58 Google Scholar
  29. Jurgens J, Ling H, Hetrick K et al (2015) Assessment of incidental findings in 232 whole-exome sequences from the Baylor-Hopkins Center for Mendelian Genomics. Genet Med Off J Am Coll Med Genet 17:782–788. doi: 10.1038/gim.2014.196 Google Scholar
  30. Landrum MJ, Lee JM, Riley GR et al (2014) ClinVar: public archive of relationships among sequence variation and human phenotype. Nucl Acids Res 42:D980–D985. doi: 10.1093/nar/gkt1113 CrossRefPubMedPubMedCentralGoogle Scholar
  31. Lawrence L, Sincan M, Markello T et al (2014) The implications of familial incidental findings from exome sequencing: the NIH Undiagnosed Diseases Program experience. Genet Med Off J Am Coll Med Genet 16:741–750. doi: 10.1038/gim.2014.29 Google Scholar
  32. Lee H, Deignan JL, Dorrani N et al (2014) Clinical exome sequencing for genetic identification of rare Mendelian disorders. JAMA 312:1880–1887. doi: 10.1001/jama.2014.14604 CrossRefPubMedPubMedCentralGoogle Scholar
  33. Lek M, Karczewski K, Minikel E et al (2015) Analysis of protein-coding genetic variation in 60,706 humans. bioRxiv, Art id 030338Google Scholar
  34. Li Y, Salfelder A, Schwab KO et al (2016) Against all odds: blended phenotypes of three single-gene defects. Eur J Hum Genet EJHG. doi: 10.1038/ejhg.2015.285 Google Scholar
  35. McCandless SE, Brunger JW, Cassidy SB (2004) The burden of genetic disease on inpatient care in a children’s hospital. Am J Hum Genet 74:121–127. doi: 10.1086/381053 CrossRefPubMedPubMedCentralGoogle Scholar
  36. Miller DT, Adam MP, Aradhya S et al (2010) Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet 86:749–764. doi: 10.1016/j.ajhg.2010.04.006 CrossRefPubMedPubMedCentralGoogle Scholar
  37. Pagon RA, Adam MP, Ardinger HH et al. (eds) (1993–2016). GeneReviews® [Internet]. University of Washington, Seattle. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1116/
  38. Philippakis AA, Azzariti DR, Beltran S et al (2015) The Matchmaker exchange: a platform for rare disease gene discovery. Hum Mutat 36:915–921. doi: 10.1002/humu.22858 CrossRefPubMedGoogle Scholar
  39. Pisano T, Numis AL, Heavin SB et al (2015) Early and effective treatment of KCNQ2 encephalopathy. Epilepsia 56:685–691. doi: 10.1111/epi.12984 CrossRefPubMedGoogle Scholar
  40. Piton A, Redin C, Mandel J-L (2013) XLID-causing mutations and associated genes challenged in light of data from large-scale human exome sequencing. Am J Hum Genet 93:368–383. doi: 10.1016/j.ajhg.2013.06.013 CrossRefPubMedPubMedCentralGoogle Scholar
  41. Posey JE, Rosenfeld JA, James RA et al (2015) Molecular diagnostic experience of whole-exome sequencing in adult patients. Genet Med Off J Am Coll Med Genet. doi: 10.1038/gim.2015.142 Google Scholar
  42. Powis Z, Farwell KD, Alamillo CL, Tang S (2015) Diagnostic exome sequencing for patients with a family history of consanguinity: over 38 % of positive results are not autosomal recessive pattern. J Hum Genet. doi: 10.1038/jhg.2015.125 PubMedGoogle Scholar
  43. Retterer K, Juusola J, Cho MT et al (2015) Clinical application of whole-exome sequencing across clinical indications. Genet Med Off J Am Coll Med Genet. doi: 10.1038/gim.2015.148 Google Scholar
  44. Richards S, Aziz N, Bale S et al (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 Off J Am Coll Med Genet 17:405–424. doi: 10.1038/gim.2015.30 Google Scholar
  45. Shashi V, McConkie-Rosell A, Rosell B et al (2014) The utility of the traditional medical genetics diagnostic evaluation in the context of next-generation sequencing for undiagnosed genetic disorders. Genet Med Off J Am Coll Med Genet 16:176–182. doi: 10.1038/gim.2013.99 Google Scholar
  46. Shashi V, McConkie-Rosell A, Schoch K et al (2015) Practical considerations in the clinical application of whole-exome sequencing. Clin Genet. doi: 10.1111/cge.12569 Google Scholar
  47. Sobreira N, Schiettecatte F, Valle D, Hamosh A (2015) GeneMatcher: a matching tool for connecting investigators with an interest in the same gene. Hum Mutat 36:928–930. doi: 10.1002/humu.22844 CrossRefPubMedPubMedCentralGoogle Scholar
  48. Soden SE, Saunders CJ, Willig LK et al (2014) Effectiveness of exome and genome sequencing guided by acuity of illness for diagnosis of neurodevelopmental disorders. Sci Transl Med 6:265ra168. doi: 10.1126/scitranslmed.3010076
  49. Stenson PD, Mort M, Ball EV et al (2014) The Human Gene Mutation Database: building a comprehensive mutation repository for clinical and molecular genetics, diagnostic testing and personalized genomic medicine. Hum Genet 133:1–9. doi: 10.1007/s00439-013-1358-4 CrossRefPubMedPubMedCentralGoogle Scholar
  50. Tammimies K, Marshall CR, Walker S et al (2015) Molecular diagnostic yield of chromosomal microarray analysis and whole-exome sequencing in children with autism spectrum disorder. JAMA 314:895–903. doi: 10.1001/jama.2015.10078 CrossRefPubMedGoogle Scholar
  51. Taylor JC, Martin HC, Lise S et al (2015) Factors influencing success of clinical genome sequencing across a broad spectrum of disorders. Nat Genet 47:717–726. doi: 10.1038/ng.3304 CrossRefPubMedPubMedCentralGoogle Scholar
  52. The 1000 Genomes Project Consortium (2015) A global reference for human genetic variation. Nature 526:68–74. doi: 10.1038/nature15393 CrossRefPubMedCentralGoogle Scholar
  53. Valencia CA, Husami A, Holle J et al (2015) Clinical impact and cost-effectiveness of whole exome sequencing as a diagnostic tool: a pediatric center’s experience. Front Pediatr 3:67. doi: 10.3389/fped.2015.00067 CrossRefPubMedPubMedCentralGoogle Scholar
  54. Wallis M, Tsurusaki Y, Burgess T et al (2015) Dual genetic diagnoses: atypical hand-foot-genital syndrome and developmental delay due to de novo mutations in HOXA13 and NRXN1. Am J Med Genet A. doi: 10.1002/ajmg.a.37478 PubMedGoogle Scholar
  55. Wright CF, Fitzgerald TW, Jones WD et al (2015) Genetic diagnosis of developmental disorders in the DDD study: a scalable analysis of genome-wide research data. Lancet Lond Engl 385:1305–1314. doi: 10.1016/S0140-6736(14)61705-0 CrossRefGoogle Scholar
  56. Yang Y, Muzny DM, Xia F et al (2014) Molecular findings among patients referred for clinical whole-exome sequencing. JAMA 312:1870–1879. doi: 10.1001/jama.2014.14601 CrossRefPubMedPubMedCentralGoogle Scholar
  57. Yavarna T, Al-Dewik N, Al-Mureikhi M et al (2015) High diagnostic yield of clinical exome sequencing in Middle Eastern patients with Mendelian disorders. Hum Genet 134:967–980. doi: 10.1007/s00439-015-1575-0 CrossRefPubMedGoogle Scholar
  58. Zhu X, Petrovski S, Xie P et al (2015) Whole-exome sequencing in undiagnosed genetic diseases: interpreting 119 trios. Genet Med Off J Am Coll Med Genet 17:774–781. doi: 10.1038/gim.2014.191 Google Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2016

Authors and Affiliations

  • Anne H. O’Donnell-Luria
    • 1
    • 2
    • 4
  • David T. Miller
    • 1
    • 3
    • 4
  1. 1.Division of Genetics and GenomicsBoston Children’s HospitalBostonUSA
  2. 2.Broad Institute of Harvard and MITCambridgeUSA
  3. 3.Claritas GenomicsCambridgeUSA
  4. 4.Harvard Medical SchoolBostonUSA

Personalised recommendations