Advertisement

The psychosocial and service delivery impact of genomic testing for inherited retinal dystrophies

  • Eleanor McVeighEmail author
  • Harriet JonesEmail author
  • Graeme Black
  • Georgina Hall
Original Article
  • 17 Downloads

Abstract

Next-generation sequencing (NGS) provides diagnostic information for many rare conditions. The evolution of NGS for panel, exome, and genome testing is set to be the platform for transforming genomic diagnosis in the National Health Service (NHS). Inherited retinal dystrophies (IRDs) are a highly genetically heterogeneous disease group causing progressive visual impairment. IRDs are ideal for an NGS panel approach due to phenotypic overlap and were one of the first diagnostic panels to be developed in the NHS. While diagnostic yield for patients with IRD has improved significantly with NGS, a proportion of patients remain without a diagnosis. The clinical value of NGS testing is well understood; however, the patient experience of panel testing is not well documented. Semi-structured qualitative telephone interviews were conducted with 23 participants with IRD who had undergone NGS testing. Interviews were transcribed verbatim and analysed using interpretative phenomenological analysis. Participants’ experiences were interpreted to explore the psychosocial and service delivery impact of this testing technology, inclusive of those who received a pathogenic, negative, carrier status or variant of uncertain significance result. Collectively, three core themes were identified: (1) the journey towards a genomic diagnosis, (2) the impact of NGS testing, (3) service delivery of NGS tests. Disclosure of results had no reported adverse implications. Participants appreciated an open discussion about the potential for an uncertain or unexpected result, prior to testing. They valued pre-test counselling discussions, expert opinions and on-going care from genomic services.

Keywords

Variant of uncertain significance Incidental findings Genomic testing Inherited retinal dystrophy Next-generation sequencing 

Notes

Acknowledgements

Fight for Sight grant ref. 1801 Improving Healthcare Provision for Patients with Inherited Retinal Diseases: An Evidence Based Approach. NHS NW 2 Research Ethics Committee (ref 10/H1005/48).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Human studies and informed consent

All procedures followed were in accordance with the ethical standards of the responsible committee on human experimentation (institutional and national) and with the Helsinki Declaration of 1975, as revised in 2000. Informed consent was obtained from all patients before being included in the study.

Supplementary material

12687_2019_406_MOESM1_ESM.docx (25 kb)
ESM 1 (DOCX 24 kb)

References

  1. Aatre RD, Day SM (2011) Psychological issues in genetic testing for inherited cardiovascular diseases. Circ Cardiovasc Genet 4:81–90Google Scholar
  2. Abdul-Karim R, Berkman BE, Wendlet D, Rid A, Khan J, Badgett T, Hull SC (2013) Disclosure of incidental findings from next-generation sequencing in paediatric genomic research. Paediatrics 131(3):564–571Google Scholar
  3. Berg JS, Khoury MJ, Evens JP (2011) Deploying whole genome sequencing in clinical practice and public: meeting the challenge one bin at a time. Gen Med 13(6):499–504Google Scholar
  4. Berger W, Kloeckener-Gruissem B, Neidhart J (2010) The molecular basis of human retinal and vitreoretinal diseases. Prog Retin Eye Res 29:335–375Google Scholar
  5. Bernhardt BA, Soucier D, Hanson K, Savage MS, Jackson L, Wapner RJ (2013) Women’s experiences receiving abnormal prenatal chromosomal microarray testing results. Gen Med : Official Journal of the American College of Medical Genetics 15(2):139–145.  https://doi.org/10.1038/gim.2012.113 Google Scholar
  6. Biesecker LG (2012) Opportunities and challenges for the integration of massively parallel genomic sequencing into clinical practice: lessons from the ClinSeq project. Gen Med 14:393–398Google Scholar
  7. Biggerstaff D, Thompson AR (2008) Interpretative phenomenological analysis (IPA): a qualitative methodology of choice in healthcare research. Qual Res Psychol 5:214–224Google Scholar
  8. Bittner A, Edwards L, George M (2010) Coping strategies to manage stress related to vision loss and fluctuations in retinitis pigmentosa. Optometry 81:461–468Google Scholar
  9. Bong C, Potrata B, Hewison J, McKibbin M (2010) Attitudes of patients and relatives/ carers towards genetic testing for inherited retinal disease. Eye 24:1622–1625Google Scholar
  10. Carss KJ, Arno G, Erwood M, Stephens J, Scanchis-Juan A, Hull S, Megy K, Grozeya D, Dewhurst E, Malka S, Plagnol V, Christopher P, Stirrups K, Rizzo R, Wright G, Josifova D, Bitner-Glindzicz M, Scott RH, Clement E, Allen L, Armstrong R, Brady AF, Carmichael J, Chitre M, Henderson RH, Hurst J, MacLaren RE, Murphy E, Paterson J, Rosser E, Thompson DA, Wakeling E, Ouwehand WH, Michaelides M, Moore AT, Webster AR (2017) Comprehensive rare variant analysis via whole-genome sequencing to determine the molecular pathology of inherited retinal disease. Am J Hum Genet 100(1):75–90Google Scholar
  11. Christenhusz MG, Devriendt K, Dierickx K (2013a) To tell or not to tell? A systematic review of ethical reflections on incidental findings arising in genetics contexts. Eur J Hum Genet 21:248–255Google Scholar
  12. Christenhusz GM, Devriendt K, Dierickz K (2013b) Disclosing incidental findings in genetic contexts: a review of the empirical ethical research. Eur J Med Gen 58:529–540Google Scholar
  13. Clift KE, Halverson CME, Fiksdal AS, Kumbamu A, Sharp RR, McCormick J (2015) Patients’ views on incidental findings from clinical exome sequencing. Appl Transl Genomics 4:38–43Google Scholar
  14. Combs R, Hall G, Payne K, Lowndes J, Devery S, Downes SM, McAllister M (2013a) Understanding the expectations of patients with inherited retinal dystrophies. Br J Ophthalmol 97:1057–1061Google Scholar
  15. Combs R, McAllister M, Payne K, Lowndes J, Devery S, Webster AR, Hall G (2013b) Understanding the impact of genetic testing for inherited retinal dystrophy. Eur J Hum Genet 21:1209–1213Google Scholar
  16. Consugar MB, Navarro-Gomez D, Place EM, Bujakowska KM, Sousa ME, Fonseca-Kelly ZD, Taub DG, Janessian M, Wang DY, Au ED, Sims KB, Sweetser DA, Fulton AB, Liu Q, Wiggs JL, Gai X, Pierce EA (2015) Panel-based genetic diagnostic testing for inherited eye diseases is highly accurate and reproducible and more sensitive for variant detection than exome sequencing. Gen Med : Official Journal of the American College of Medical Genetics 17(4):253–261Google Scholar
  17. Cornelis c, Tibben A, Dondorp W, Halest M, Bredenoord AL, Knoers N, Duwell M, Bolt J, Van Summeren M (2016) Whole-exome sequencing in paediatrics: parents’ considerations toward return of unsolicited findings for their child. Eur J Hum Genet 24:1681–1687Google Scholar
  18. Crawford G, Foulds N, Fenwick A, Hallowell N, Lucassen A (2013) Genetic medicine and incidental findings: it is more complicated than deciding whether to disclose or not. Gen Med 15(11):896–899Google Scholar
  19. Daiger S, Suliva L, Bowne S (2014) Genes and mutations causing retinitis pigmentosa. Clin Genet 84(2):1–16Google Scholar
  20. Davison N, Payne K, Eden M, McAllister M, Roberts SA, Ingram S, Black GC, Hall G (2017) Exploring the feasibility of delivering standardised genomic care using ophthalmology as an example. Gen Med 19:1032–1039.  https://doi.org/10.1038/gim.2017.9(advancedpublication) Google Scholar
  21. Department of Health & Social Care (2018) Government response to the House of Commons Science and Technology Committee’s third report of session 2017–2019, “Genomics and Genome Editing in the NHS”. Crown Copyright www.gov.uk/government/publications/ Last Accessed: 25/07/2018
  22. Ellard S, Baple EL, Owens M, Eccles DM, Abbs S, Deans ZC, Newman WG, McMullan DJ (2017) ACGS best practice guidelines for variants classification 2017 – consensus statement. Association for Clinical Genetic Science, Part of the British Society for Genomic MedicineGoogle Scholar
  23. Ellingford JM, Barton S, Bhaskar S, Williams SG, Sergouniotis PI, O'Sullivan J, Lamb JA, Perveen R, Hall G, Newman WG, Bishop PN, Roberts SA, Leach R, Tearle R, Bayliss S, Ramsden SC, Nemeth AH, Black GCM (2016) Whole genome sequencing increases molecular diagnostic yield compared with current diagnostic testing for inherited retinal disease. Ophthalmology 123(5):1143–1150Google Scholar
  24. Facio FM, Lee K, O’Daniel JM (2014) A genetic counsellor’s guide to using next generation sequencing in clinical practice. J Genet Couns 23:455–462Google Scholar
  25. Fight for Sight (2014) Statistics about sight loss and eye disease. https://www.fightforsight.org.uk/about-the-eye/facts-about-sight-loss/ Last accessed: 21/01/2018
  26. Fischer MD, McClements ME, de la Martinez-Fernandez Camara C, Bellingrath JS, Dauletbetov D, Ramsden SC, Hickey HG, Barnard AR, Mac Laren RE (2017) Codon-optimized RPGR improves stability and efficacy of AAV8 Gene therapy in two mouse models of X-linked retinitis pigmentosa. Mol Ther 25(8):1854–1865Google Scholar
  27. Gillespie RL, Hall G, Black GC (2014) Genetic testing for inherited ocular disease: delivering on the promise at last? Clin Exp Ophthalmol 42:65–77Google Scholar
  28. Glöckle N, Kohl S, Mohr J, Scheurenbrand T, Sprecher A, Weisschult N, Bernd A, Rudolph G, Schubach M, Poloschelt C, Zrenner E, Biskup S, Berger W, Wissinger B, Meidhardt J (2014) Panel-based next generation sequencing as a reliable and efficient technique to detect mutations in unselected patients with retinal dystrophies. Eur J Hum Genet 22:95–140Google Scholar
  29. Green RC, Berg JS, Grody WW, Kalia SS, Korf BR, Martin CL, McGuire A, Nussbaum RL, O’Daniel JM, Ormond KE, Rehm HL, Watson MS, Williams MS, Biesecker LG (2013) ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Gen Med 15(7):565–574Google Scholar
  30. Halverson ME, Clift KE, McCormick JB (2016) Was it worth it? Patients’ perspectives on the perceived value of genomic-based individualized medicine. J Commun Gen 7:145–152Google Scholar
  31. Hayeems RZ, Geller G, Finkelstein D, Faden RR (2005) How patients experience progressive loss of visual function: a model of adjustment using qualitative methods. Br J Ophthalmol 89:615–620Google Scholar
  32. Hayeems RZ, Miller FA, Li L, Bytautas JP (2001) Not so simple: a quasi-experimental study of how researchers adjudicate genetic research result. Eur J Hum Genet 19:740–747Google Scholar
  33. Heshka JT, Palleschi C, Howley H, Wilson B, Wells PS (2008) A systematic review of perceived risks, psychological and behavioral impacts of genetic testing. Gen Med 10:19–32Google Scholar
  34. 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 91:97–108Google Scholar
  35. Koenekoop RK, Lopez I, Den Hollander AI, Allikmets R, Cremers FP (2007) Genetic testing for retinal dystrophies and dysfunctions: benefits, dilemmas and solutions. Clin Exp Ophthalmol 35:473–485Google Scholar
  36. Lubin IM, McGovern MM, Gibson Z, Gross SJ, Pratt VM, Rashid J, Shaw C, Stoddard L, Trotter TL, Williams MS, Wilson JA, Pass K (2009) Clinician perspectives about molecular genetic testing for heritable conditions and development of clinician-friendly laboratory report. J Mol Diagn 11(2):162–171Google Scholar
  37. Marx V (2015) The DNA of a nation. Nature 524:503–505Google Scholar
  38. Massof RW, Ahmadian L, Grover LI, Deremeik J, Goldstein JE, Rainey C, Epstein C, Garnet GD (2007) The activity inventory: an adaptive visual function questionnaire. Optom Vis Sci 84:763–774Google Scholar
  39. McAllister M, Dunn G, Todd C (2011) Empowerment: qualitative underpinning of a new clinical genetics-specific patient-reported outcome. Eur J Hum Genet 19:125–130Google Scholar
  40. Meiser B, Butow P, Friedlander MM, Barratt A, Schnieden V, Watson M, Brown J, Tucker K (2002) Psychological impact of genetic testing in women from high-risk breast cancer families. Eur J Cancer 38:2025–2031Google Scholar
  41. Metzker ML (2010) Sequencing technologies - the next generation. Nat Rev Genet 11(1):31–46Google Scholar
  42. Moore T, Burton H (2008) Report for the United Kingdom Genetic Testing Network: a needs assessment and review of specialist services for genetic eye disorders. PHG foundation, Genetic Ophthalmology in Focus Google Scholar
  43. Novick G (2008) Is there a bias against telephone interviews in qualitative research? Res Nurs Health 31(4):391–398Google Scholar
  44. O’Sullivan J, Mullaney BG, Bhaskar SS, Dickerson JE, Hall G, O’Grady A, Black GC (2012) A paradigm shift in the delivery of services for diagnosis of inherited retinal disease. J Med Genet 49(5):322–326Google Scholar
  45. Pope C, Ziebland S, Mays N (2000) Qualitative research in health care: analysing qualitative data. Br Med J 320:5–7Google Scholar
  46. Pringle J, Drummond J, McLafferty E, Hendry C (2011) Interpretative phenomenological analysis: a discussion and critique. Nurs Res 18(3):20–24Google Scholar
  47. Raza S, Luheshi L, Hall A, Baple E, Ellard S, McMullan D (2017) Variant classifications and interpretation – workshop report. PHG Foundation. ISBN 978-1-907198-26-7Google Scholar
  48. Reiff M, Bernhardt BA, Mulchandani S, Soucier D, Cornell D, Pyeritz RE, Spinner NB (2012) “What does it mean?”: uncertainties in understanding results of chromosomal microarray testing. Gen Med : Official Journal of the American College of Medical Genetics 14(2):250–258Google Scholar
  49. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, Grody WW, Hedge M, Lyon E, Spector E, Voelkerding K, Rehm HL, ACGM 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 of Molecular Pathology. Gen Med 7(5):405–424Google Scholar
  50. RNIB (2014) Coming to terms with sight loss. Royal National Institute of Blind People, https://www.rnib.org.uk/recently-diagnosed/coming-terms-sight-loss. Accessed 23 Jan 2019
  51. Shanks ME, Downes SM, Copley RR, Lise S, Broxholme J, Hudspith KAZ, … Ragoussis J, Nemeth AH (2013) Next generation sequencing (NGS) as a diagnostic tool for retinal degeneration reveals a much higher detection rate in early-onset disease. Eur J Hum Genet, 21, 274–280Google Scholar
  52. Slade J (2014) Early intervention support in eye clinics. an overview of emotional and practical support in UK eye clinics for the year 2012/13. RNIB Early Intervention Support Network Google Scholar
  53. Smith JA, Osborn M (2003) Interpretative phenomenological analysis. In: Smith JA (ed) Qualitative psychology: a practical guide to methods. Sage, LondonGoogle Scholar
  54. Staley K (2009) Exploring impact: public involvement in NHS, public health and social care research. INVOLVE, EastleighGoogle Scholar
  55. Stavropoulos DJ, Merico D, Jobling R, Bowdin S, Monfared N, Thiruvahindrapuram B, Nalpathamkalam T, Pellecchia G, Yuen RKC, Szego MJ, Hayeems RZ, Shaul RZ, Brudno M, Girdea M, Frey B, Alipanahi B, Ahmed S, Babul-Hirji R, Porras RB, Carter MT, Chad L, Chaudhry A, Chitayat D, Doust SJ, Cytrynbaum C, Dupuis L, Ejaz R, Fishman L, Guerin A, Hashemi B, Helal M, Hewson S, Inbar-Feigenberg M, Kannu P, Karp N, Kim RH, Kronick J, Liston E, MacDonald H, Mercimek-Mahmutoglu S, Mendoza-Londono R, Nasr E, Nimmo G, Parkinson N, Quercia N, Raiman J, Roifman M, Schulze A, Shugar A, Shuman C, Sinajon P, Siriwardena K, Weksberg R, Yoon G, Carew C, Erickson R, Leach RA, Klein R, Ray PN, Meyn MS, Scherer SW, Cohn RD, Marshall CR (2016) Whole genome sequencing expands diagnostic utility and improves clinical management in pediatric medicine. NPJ Genomic Med 1:15012Google Scholar
  56. Stone EM (2007) Genetic testing for inherited eye disease. Arch Ophthalmol 125:205–212Google Scholar
  57. Veltel S, Gasper R, Eisenacher E, Wittinghofer A (2008) The retinitis pigmentosa 2 gene product is a GTPase-activating protein for Arf-like 3. Nat Struct Mol Biol 15:373–380Google Scholar
  58. Wallis Y, Payne S, McAnulty C, Bodmer D, Sistermans E, Robertson K, Moore D, Abbs S, Deans Z & Devereau A (2013) Practice guidelines for the evaluation of pathogenicity and the reporting of sequence variants in clinical molecular genetics. Assoc Clin Gen Sci, p. 1–16Google Scholar
  59. Westerfield L, Darilek S, van den Veyver IB (2014) Counselling challenges with variants of uncertain significance and incidental findings in prenatal genetic screening and diagnosis. J Clin Med 3(3):1018–1032Google Scholar
  60. Wildeman M, van Ophuizen E, den Dunnen JT, Taschner PEM (2008) Improving sequence variant descriptions in mutation databases and literature using the Mutalyzer sequence variation nomenclature checker. Hum Mutat 29(1):6–13Google Scholar
  61. Willis TA, Potrata B, Ahmed M, Hewison J, Gale R, Downey L, McKibbin M (2013) Understanding of and attitudes to genetic testing for inherited retinal disease: a patient perspective. BMJ, Br J Ophthalmol 00:1–7Google Scholar

Copyright information

© Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  1. 1.Clinical Genetics ServiceBirmingham Women’s and Children’s NHS Foundation Trust, Birmingham Women’s HospitalBirminghamUK
  2. 2.Genetics Health Service, Northern HubAuckland City HospitalAuklandNew Zealand
  3. 3.Manchester Centre for Genomic Medicine, Central Manchester University Hospitals NHS Foundation TrustSt Mary’s HospitalManchesterUK

Personalised recommendations