Этические проблемы геномного скрининга: обзор литературы

Полногеномное и полноэкзомное секвенирование имеет общепризнанную клиническую значимость для диагностики орфанных заболеваний. Вследствие развития технологии секвенирования и последующего снижения затрат на тестирование, данные методы все чаще используются не только в клинических целях, но и в качестве инструмента скрининга здоровых индивидов. При проведении исследования по поводу подозрения на генетическое заболевание в семье и при тестировании здорового человека «по желанию» могут быть выявлены «случайные находки» с разной клинической значимостью. Однако в ряде профессиональных руководств появились рекомендации по систематическому поиску клинически значимых вторичных результатов - так называемому оппортунистическому скринингу. В соответствии с этим активно обсуждаются этические проблемы оппортунистического скрининга в контексте соразмерности пользы и рисков для тестируемого человека, информированного согласия и защиты его автономии и справедливости. Этические проблемы в связи с клиническим использованием анализа генома в Российской Федерации мало изучены. В данной обзорной статье описываются упомянутые проблемы и на основе международного опыта.

полногеномное секвенирование, полноэкзомное секвенирование, оппортунистический генетический скрининг, этические проблемы

1. Biesecker, L.G., Green, R.C. Diagnostic clinical genome and exome sequencing. N Engl J Med. 2014; 370: 2418-2425.

2. Porta-Pardo E., Valencia A., Godzik, A. Understanding oncogenicity of cancer driver genes and mutations in the cancer genomics era. FEBS Lett. 2020; 594(24):4233-4246. doi:10.1002/1873-3468.13781

3. Gregg A.R. Expanded carrier screening. Obstet Gynecol Clin North Am. 2018; 45:103-112.

4. Adams M.C., Evans J.P., Henderson G.E., Berg J.S. The promise and peril of genomic screening in the general population. Genet Med. 2016;18(6):593-9.

5. Zoltick E.S., Linderman M.D., McGinniss M.A., et al. Predispositional genome sequencing in healthy adults: design, participant characteristics, and early outcomes of the PeopleSeq Consortium. Genome Med. 2019;11(1):10. doi:10.1186/s13073-019-0619-9

6. Pinxten W., Howard H.C. Ethical issues raised by whole genome sequencing. Best Pract Res Clin Gastroenterol. 2014 Apr;28(2):269-79. doi: 10.1016/j.bpg.2014.02.004.

7. Cooper D.N., Krawczak M., Polychronakos C., Tyler-Smith C., Kehrer-Sawatzki H. Where genotype is not predictive of phenotype: towards an understanding of the molecular basis of reduced penetrance in human inherited disease. Hum Genet. 2013;132(10):1077-130.

8. Voorwinden J.S., Buitenhuis A.H., Birnie E., et al. Expanded carrier screening: what determines intended participation and can this be influenced by message framing and narrative information?. Eur J Hum Genet. 2017;25(7):793-800. doi:10.1038/ejhg.2017.74

9. Manrai, A.K., Funke, B.H., Rehm, H.L. et al. Genetic misdiagnoses and the potential for health disparities. N Engl J Med. 2016; 375: 655-665.

10. Van Driest S.L., Wells Q.S., Stallings S. et al. Association of arrhythmia-related genetic variants with phenotypes documented in electronic medical records. JAMA. 2016; 315: 47-57.

11. Cassa C.A., Tong M.Y., Jordan D.M. Large numbers of genetic variants considered to be pathogenic are common in asymptomatic individuals. Hum Mutat. 2013; 34: 1216-1220.

12. Christensen K.D., Dukhovny D., Siebert U., Green RC. Assessing the costs and cost-effectiveness of genomic sequencing. J Pers Med. 2015;5(4):470-86.

13. Goldfeder R.L., Wall D.P., Khoury M.J., Ioannidis J.P.A., Ashley E.A. Human genome sequencing at the population scale: a primer on high-throughput DNA sequencing and analysis. Am J Epidemiol. 2017; 186: 1000-1009.

14. Butterfield R.M., Evans J.P., Rini C., et al. Returning negative results to individuals in a genomic screening program: lessons learned. Genet Med. 2019;21(2):409-416.

15. Захарова Е.Ю., Ижевская В.Л., Байдакова Г.В., Иванова Т.А., Чумакова О.В., Куцев С.И. Массовый скрининг на наследственные болезни: ключевые вопросы. Медицинская генетика. 2017;16(10):3-13.

16. Scherokman B. Selecting and interpreting diagnostic tests. The Permanente Journal. 1997;1(2):4-7.

17. Hart M.R., Biesecker B.B., Blout C.L., et al. Secondary findings from clinical genomic sequencing: prevalence, patient perspectives, family history assessment and healthcare costs from a multi-site study. Genet Med. 2019;21(5):1100-1110.

18. Lebo M.S., Yu T.W., Fayer S., et al. Genomic sequencing reveals previously unrecognized phenotypes in a high proportion of those with unanticipated monogenic disease risk. Presented at: American Society of Human Genetics, San Diego, California, October 17, 2018.

19. Green R.C., Berg J.S., Grody W.W. et al. American College of Medical Genetics and Genomics. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med. 2013; 15: 565-574.

20. Green R.C., Lupski J.R., Biesecker L.G. Reporting genomic sequencing results to ordering clinicians: incidental, but not exceptional. JAMA. 2013; 310: 365-366.

21. ACMG Board of Directors. ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing. Genet Med. 2015; 17: 68-69.

22. Kalia S.S., Adelman K., Bale S.J. et al. 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. 2017; 19: 249-255.

23. Van El C.G., Cornel M.C., Borry P., Hastings R.J., Fellmann F., Hodgson S.V., et al. Public and Professional Policy Committee. Whole-genome sequencing in health care: recommendations of the European Society of Human Genetics. Eur J Hum Genet. 2013;21:580-4.

24. de Wert, G., Dondorp, W., Clarke, A. et al. Opportunistic genomic screening. Recommendations of the European Society of Human Genetics. Eur J Hum Genet. 2021; 29, 365-377. https://doi.org/10.1038/s41431-020-00758-w

25. Рыжкова О.П., Кардымон О.Л., Прохорчук Е.Б., Коновалов Ф.А., Масленников А.Б., Степанов В.А., Афанасьев А.А., Заклязьминская Е.В., Ребриков Д.В., Савостьянов К.В., Глотов А.С., Костарева А.А., Павлов А.Е., Голубенко М.В., Поляков А.В., Куцев С.И. Руководство по интерпретации данных последовательности ДНК человека, полученных методами массового параллельного секвенирования (MPS) (редакция 2018, версия 2). Медицинская генетика. 2019;18(2):3-23.

26. Scripps Center for Executive Health Genetic testing. San Diego, CA: Scripps Health; 2015.

27. Linderman M.D., Nielsen D.E., Green R.C. Personal genome sequencing in ostensibly healthy individuals and the PeopleSeq Consortium. J Pers Med. 2016; 6 (2):14.

28. Foulkes W.D., Knoppers B.M., Turnbull, C. Population genetic testing for cancer susceptibility: founder mutations to genomes. Nat Rev Clin Oncol. 2016; 13: 41-54.

29. Adams M.C., Berg J.S., Pearlman M.D., Vora N.L. Look before you leap: genomic screening in obstetrics and gynecology. Obstet Gynecol. 2015; 125: 1299-1305.

30. Stavropoulos D.J., Merico D., Jobling R., et al. Whole Genome Sequencing Expands Diagnostic Utility and Improves Clinical Management in Pediatric Medicine. NPJ Genom Med. 2016;1:15012. doi:10.1038/npjgenmed.2015.12

31. ACMG Board of Directors. Points to consider in the clinical application of genomic sequencing. Genet Med. 2012; 14: 759-761.

32. Home - U.S. Preventive Services Task Force. Vol. 2016. Rockville, MD: USPSTF Program Office; 2014.

33. Tsubono Y., Hisamichi S. A halt to neuroblastoma screening in Japan. N Engl J Med. 2004; 350: 2010-2011.

34. McGrath S.P., Coleman J., Najjar L., Fruhling A., Bastola D.R. Comprehension and data-sharing behavior of direct-to-consumer genetic test customers. Public Health Genomics. 2016; 19: 116-124.

35. Krieger J.L., Murray F., Roberts J.S., Green R.C. The impact of personal genomics on risk perceptions and medical decision-making. Nat Biotechnol. 2016; 34: 912-918.

36. van der Hout S., Holtkamp K.C., Henneman L., de Wert G., Dondorp W.J. Advantages of expanded universal carrier screening: what is at stake?. Eur J Hum Genet. 2016;25(1):17-21. doi:10.1038/ejhg.2016.12535.

37. Mathijssen I.B., Holtkamp K.C.A., Ottenheim C.P.E., et al. Preconception carrier screening for multiple disorders: evaluation of a screening offer in a Dutch founder population. Eur J Hum Genet. 2019;26(2):166-175. doi:10.1038/s41431-017-0056-4

38. Abul-Husn N.S., Manickam K., Jones L.K., Wright E.A., Hartzel D.N, GonzagaJauregui C, et al. Genetic identification of familial hypercholesterolemia within a single U.S. health care system. Science. 2016;354(6319):aaf7000. doi: 10.1126/science.aaf7000. PMID: 28008010.

39. Perkins B.A., Caskey C.T., Brar P., Dec E., Karow D.S., Kahn A.M., et al. Precision medicine screening using whole-genome sequencing and advanced imaging to identify disease risk in adults. Proc Natl Acad Sci U S A. 2018; 115(14):3686-91.

40. Dewey F.E., Murray M.F., Overton J.D., Habegger L., Leader J.B., Fetterolf S.N., et al. Distribution and clinical impact of functional variants in 50,726 whole exome sequences from the DiscovEHR study. Science. 2016;354(6319): aaf6814. https://doi.org/10.1126/science.aaf6814.

41. Vassy J.L., Christensen K.D., Schonman E.F., Blout C.L., Robinson J.O., Krier J.B., et al. The impact of whole-genome sequencing on the primary care and outcomes of healthy adult patients: a pilot randomized trial. Ann Intern Med. 2017;167(3):159-69.

42. Johnston J.J., Lewis K.L., Ng D., Singh L.N., Wynter J., Brewer C., et al. Individualized iterative phenotyping for genome-wide analysis of loss-offunction mutations. Am J Hum Genet. 2015;96(6):913-25.

43. Collins F.S., Varmus H. A new initiative on precision medicine. N Engl J Med. 2015;372(9):793-795.

44. Botkin J.R., Belmont J.W., Berg J.S., et al. Points to consider: ethical, legal, and psychosocial implications of genetic testing in children and adolescents. Am J Hum Genet. 2015;97(1):6-21.

45. Goldenberg A.J., Dodson D.S., Davis M.M., Tarini B.A. Parents’ interest in whole genome sequencing of newborns. Genet Med. 2014;16(1):78-84.

46. Roche M.I., Berg J.S. Incidental findings with genomic testing: implications for genetic counseling practice. Curr Genet Med Rep. 2015;3(4):166-176.

47. Waisbren S.E., Bäck D.K., Liu C., et al. Parents are interested in newborn genomic testing during the early postpartum period. Genet Med. 2015;17(6):501-504

48. Van Steijvoort E., Chokoshvili D, Cannkn D.W., et al. Interest in expanded carrier screening among individuals and couples in the general population: systematic review of the literature. Hum Reprod Update. 2020 Feb 25. pii: dmaa001. doi: 10.1093/humupd/dmaa001.

49. VanNoy G.E., Genetti C.A., McGuire A.L., Green R.C., Beggs A.H., Holm I.A.; BabySeq Project Group. Challenging the Current Recommendations for Carrier Testing in Children. Pediatrics. 2019 Jan;143(Suppl 1):S27-S32. doi: 10.1542/peds.2018-1099F.

50. Wang T., Ma J., Zhang Q., et al. Expanded Newborn Screening for Inborn Errors of Metabolism by Tandem Mass Spectrometry in Suzhou, China: Disease Spectrum, Prevalence, Genetic Characteristics in a Chinese Population. Front Genet. 2019;10:1052. Published 2019 Oct 29. doi:10.3389/fgene.2019.01052

51. Boone P. M. Adolescents, Family History, and Inherited Disease Risk: An Opportunity. Pediatrics; 2016, 138 (2): e20160579. DOI: 10.1542/peds.2016-0579

52. Vears D.F., Metcalfe S.A. Carrier testing in children and adolescents. Eur J Med Genet. 2015;58(12):659-67. doi: 10.1016/j.ejmg.2015.11.006.

53. Malpas P.J. Why tell asymptomatic children of the risk of an adult-onset disease in the family but not test them for it? J Med Ethics 2006; 32: 639 - 642.

54. Wilfond B.S., Fernandez C.V., Green R.C. Disclosing secondary fi ndings from pediatric sequencing to families: considering the “benefi t to families”. J Law Med Ethics. 2015;43(3):552-558.

55. Bredenoord A.L., de Vries M.C., van Delden H. The right to an open future concerning genetic information. Am J Bioeth. 2014;14(3):21-23.

56. Летов О. В. Этические принципы исследований в области генетики. Культурология. 2007; 4: 26-4

57. Ross L.F., Clayton E.W. Ethical Issues in Newborn Sequencing Research: The Case Study of BabySeq. Pediatrics. 2019 Dec;144(6): e20191031. doi: 10.1542/peds.2019-1031.

58. Ceyhan-Birsoy O., Murry J.B., Machini K., Lebo M.S., Yu T.W., Fayer S., Genetti C.A., Schwartz T.S., Agrawal P.B., Parad R.B., Holm I.A., McGuire A.L., Green R.C., Rehm H.L., Beggs A.H.; BabySeq Project Team. Interpretation of Genomic Sequencing Results in Healthy and Ill Newborns: Results from the BabySeq Project. Am J Hum Genet. 2019;104(1):76-93. doi: 10.1016/j.ajhg.2018.11.016.

59. Adhikari A.N., Gallagher R.C., Wang Y. et al. The role of exome sequencing in newborn screening for inborn errors of metabolism. Nat Med. 2020; 26: 1392-1397. https://doi.org/10.1038/s41591-020-0966-5

60. Bunnik E.M., de Jong A., Nijsingh N., et al. The new genetics and informed consent: differentiating choice to preserve autonomy. Bioethics 2013;27(6):348-55

61. Parker M., Lucassen A. Using a genetic test result in the care of family members: how does the duty of confidentiality apply?. Eur J Hum Genet. 2018; 26: 955-959. (2018). https://doi.org/10.1038/s41431-018-0138-y

62. Horn R., Parker M. Opening Pandora’s box?: ethical issues in prenatal whole genome and exome sequencing. Prenat Diagn. 2018;38(1):20-25. doi:10.1002/pd.5114

63. Practice Committee of the American Society for Reproductive Medicine, Practice Committee of the Society for Assisted Reproductive Technology. Recommendations for gamete and embryo donation: a committee opinion. Fertil Steril. 2013;99:47-62.

64. Zhang T., Madeira J., Lu Y. Expanded Preconception Carrier Screening in Clinical Practice: Review of Technology, Guidelines, Implementation Challenges, and Ethical Quandaries. Clin Obstet Gynecol. 2019 Jun;62(2):217-227. doi: 10.1097/GRF.0000000000000437.

65. Silver A.J., Larson J.L., Silver M.J., Lim R.M., Borroto C., Spurrier B., et al. Carrier screening is a deficient strategy for determining sperm donor eligibility and reducing risk of disease in recipient children. Genet Test Mol Biomarkers. 2016;20:276-84.