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Genomics for the Neonatologist

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Emerging Topics and Controversies in Neonatology

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Abstract

Genomics is the study of an individual’s entire genetic code, in contrast to traditional genetics, which focuses on specific genes. Advances in DNA sequencing technologies have led to the development of the field of genomic medicine, which applies to nearly all medical specialities. The cost of whole genome sequencing is falling rapidly and meaningful results can be obtained from a blood sample in increasingly shorter timeframes. The importance of genetic variation in the pathogenesis of common neonatal conditions is beginning to be elucidated and the utility of genomic medicine in the management of acutely ill children on the neonatal unit has been shown in numerous recent studies.

This chapter initially provides a brief overview of genomic concepts to orientate the reader in the field. An overview of the rapidly advancing field of genomic diagnostics is provided with examples showing the benefits of using genomics to guide management on the neonatal unit. Finally, the ethical considerations around genomic medicine are explored.

The 100,000 Genomes Project in the UK is being mirrored by numerous other large scale sequencing projects around the world. A key goal of the 100,000 Genomes Project is that it will embed the infrastructure necessary for widespread genomic analysis to be used on patients with rare diseases and cancer within the National Health Service in the UK. Increasingly, genetic and genomic tests are being ‘mainstreamed’ to specialities outside of clinical genetics.

Adoption of genomic diagnostics is already in use in an increasing number of neonatal units around the globe. As the 100,000 Genomes Project moves to completion, the costs of whole genome sequencing will continue to fall and genomic analysis will be available within mainstream medicine. An understanding of the benefits, risks, limitations and ethical considerations surrounding genomic medicine will be essential for all neonatologists.

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References

  1. Stevenson DA, Carey JC. Contribution of malformations and genetic disorders to mortality in a children’s hospital. Am J Med Genet A. 2004;126A(4):393–7.

    Article  PubMed  Google Scholar 

  2. Petrikin JE, Willig LK, Smith LD, Kingsmore SF. Rapid whole genome sequencing and precision neonatology. Semin Perinatol. 2015;39(8):623–31.

    Article  PubMed  PubMed Central  Google Scholar 

  3. Sheridan E, Wright J, Small N, Corry PC, Oddie S, Whibley C, et al. Risk factors for congenital anomaly in a multiethnic birth cohort: an analysis of the Born in Bradford study. Lancet. 2013;382(9901):1350–9.

    Article  PubMed  Google Scholar 

  4. Synnes AR, Berry M, Jones H, Pendray M, Stewart S, Lee SK, et al. Infants with congenital anomalies admitted to neonatal intensive care units. Am J Perinatol. 2004;21(4):199–207.

    Article  PubMed  Google Scholar 

  5. Berry MA, Shah PS, Brouillette RT, Hellmann J. Predictors of mortality and length of stay for neonates admitted to children’s hospital neonatal intensive care units. J Perinatol. 2008;28(4):297–302.

    Article  CAS  PubMed  Google Scholar 

  6. Willig LK, Petrikin JE, Smith LD, Saunders CJ, Thiffault I, Miller NA, et al. Whole-genome sequencing for identification of Mendelian disorders in critically ill infants: a retrospective analysis of diagnostic and clinical findings. Lancet Respir Med. 2015;3(5):377–87.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Meng L, Pammi M, Saronwala A, Magoulas P, Ghazi AR, Vetrini F, et al. Use of exome sequencing for infants in intensive care units: ascertainment of severe single-gene disorders and effect on medical management. JAMA Pediatr. 2017;171(12):e173438.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Daoud H, Luco SM, Li R, Bareke E, Beaulieu C, Jarinova O, et al. Next-generation sequencing for diagnosis of rare diseases in the neonatal intensive care unit. CMAJ. 2016;188(11):E254–60.

    Article  PubMed  PubMed Central  Google Scholar 

  9. Lee H, Deignan JL, Dorrani N, Strom SP, Kantarci S, Quintero-Rivera F, et al. Clinical exome sequencing for genetic identification of rare Mendelian disorders. JAMA. 2014;312(18):1880–7.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  10. Posey JE, Harel T, Liu P, Rosenfeld JA, James RA, Coban Akdemir ZH, et al. Resolution of disease phenotypes resulting from multilocus genomic variation. N Engl J Med. 2017;376(1):21–31.

    Article  CAS  PubMed  Google Scholar 

  11. Trujillano D, Bertoli-Avella AM, Kumar Kandaswamy K, Weiss ME, Köster J, Marais A, et al. Clinical exome sequencing: results from 2819 samples reflecting 1000 families. Eur J Hum Genet. 2017;25(2):176–82.

    Article  CAS  PubMed  Google Scholar 

  12. Yang Y, Muzny DM, Xia F, Niu Z, Person R, Ding Y, et al. Molecular findings among patients referred for clinical whole-exome sequencing. JAMA. 2014;312(18):1870–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Stark Z, Tan TY, Chong B, Brett GR, Yap P, Walsh M, et al. A prospective evaluation of whole-exome sequencing as a first-tier molecular test in infants with suspected monogenic disorders. Genet Med. 2016;18(11):1090–6.

    Article  CAS  PubMed  Google Scholar 

  14. Lionel AC, Costain G, Monfared N, Walker S, Reuter MS, Hosseini SM, et al. Improved diagnostic yield compared with targeted gene sequencing panels suggests a role for whole-genome sequencing as a first-tier genetic test. Genet Med. 2018;20(4):435–43.

    Article  CAS  PubMed  Google Scholar 

  15. Stavropoulos DJ, Merico D, Jobling R, Bowdin S, Monfared N, Thiruvahindrapuram B, et al. Whole genome sequencing expands diagnostic utility and improves clinical management in pediatric medicine. NPJ Genom Med. 2016;1:15012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Farnaes L, Hildreth A, Sweeney NM, Clark MM, Chowdhury S, Nahas S, et al. Rapid whole-genome sequencing decreases infant morbidity and cost of hospitalization. NPJ Genom Med. 2018;3:10.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  17. Saunders CJ, Miller NA, Soden SE, Dinwiddie DL, Noll A, Alnadi NA, et al. Rapid whole-genome sequencing for genetic disease diagnosis in neonatal intensive care units. Sci Transl Med. 2012;4(154):154ra135.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  18. Miller NA, Farrow EG, Gibson M, Willig LK, Twist G, Yoo B, et al. A 26-hour system of highly sensitive whole genome sequencing for emergency management of genetic diseases. Genome Med. 2015;7:100.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  19. Stark Z, Schofield D, Alam K, Wilson W, Mupfeki N, Macciocca I, et al. Prospective comparison of the cost-effectiveness of clinical whole-exome sequencing with that of usual care overwhelmingly supports early use and reimbursement. Genet Med. 2017;19(8):867–74.

    Article  PubMed  Google Scholar 

  20. Schwarze K, Buchanan J, Taylor JC, Wordsworth S. Are whole-exome and whole-genome sequencing approaches cost-effective? A systematic review of the literature. Genet Med. 2018;20(10):1122–30.

    Article  PubMed  Google Scholar 

  21. Graungaard AH, Skov L. 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. 2007;33(3):296–307.

    Article  CAS  PubMed  Google Scholar 

  22. Taanila A, Syrjälä L, Kokkonen J, Järvelin M-R. Coping of parents with physically and/or intellectually disabled children. Child Care Health Dev. 2002;28(1):73–86.

    Article  CAS  PubMed  Google Scholar 

  23. NICUSeq: a trial to evaluate the clinical utility of human whole genome sequencing (WGS) compared to standard of care in acute care neonates and infants—full text view—ClinicalTrials.gov [Internet]. [Cited 2018 Nov 25]. https://clinicaltrials.gov/ct2/show/NCT03290469.

  24. Connell TG, Rele M, Cowley D, Buttery JP, Curtis N. How reliable is a negative blood culture result? Volume of blood submitted for culture in routine practice in a children’s hospital. Pediatrics. 2007;119(5):891–6.

    Article  PubMed  Google Scholar 

  25. McCabe KM, Khan G, Zhang YH, Mason EO, McCabe ER. Amplification of bacterial DNA using highly conserved sequences: automated analysis and potential for molecular triage of sepsis. Pediatrics. 1995;95(2):165–9.

    CAS  PubMed  Google Scholar 

  26. Jordan JA, Durso MB. Real-time polymerase chain reaction for detecting bacterial DNA directly from blood of neonates being evaluated for sepsis. J Mol Diagn. 2005;7(5):575–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Pammi M, Flores A, Leeflang M, Versalovic J. Molecular assays in the diagnosis of neonatal sepsis: a systematic review and meta-analysis. Pediatrics. 2011;128(4):e973–85.

    Article  PubMed  Google Scholar 

  28. Su G, Fu Z, Hu L, Wang Y, Zhao Z, Yang W. 16S ribosomal ribonucleic acid gene polymerase chain reaction in the diagnosis of bloodstream infections: a systematic review and meta-analysis. PLoS One. 2015;10(5):e0127195.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  29. Pammi M, Flores A, Versalovic J, Leeflang MM. Molecular assays for the diagnosis of sepsis in neonates. Cochrane Database Syst Rev. 2017;2:CD011926.

    PubMed  Google Scholar 

  30. Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. 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. 2015;17(5):405–24.

    Article  PubMed  PubMed Central  Google Scholar 

  31. Green RC, Berg JS, Grody WW, Kalia SS, Korf BR, Martin CL, et al. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med. 2013;15(7):565–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. 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(1):68–9.

    Article  Google Scholar 

  33. Matthijs G, Souche E, Alders M, Corveleyn A, Eck S, Feenstra I, et al. Guidelines for diagnostic next-generation sequencing. Eur J Hum Genet. 2016;24(1):2–5.

    Article  CAS  PubMed  Google Scholar 

  34. Deciphering Developmental Disorders Study. Prevalence and architecture of de novo mutations in developmental disorders. Nature. 2017;542(7642):433–8.

    Article  CAS  Google Scholar 

  35. van der Sluijs EPJ, Jansen S, Vergano SA, Adachi-Fukuda M, Alanay Y, AlKindy A, et al. The ARID1B spectrum in 143 patients: from nonsyndromic intellectual disability to Coffin-Siris syndrome. Genet Med. 2019;21(6):1295–307.

    Article  PubMed  CAS  Google Scholar 

  36. Leonard H, Eastham K, Dark J. Heart and heart-lung transplantation in Down’s syndrome. BMJ. 2000;320(7238):816–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Richards CT, Crawley LM, Magnus D. Use of neurodevelopmental delay in pediatric solid organ transplant listing decisions: inconsistencies in standards across major pediatric transplant centers. Pediatr Transplant. 2009;13(7):843–50.

    Article  PubMed  Google Scholar 

  38. Ayuso C, Millán JM, Mancheño M, Dal-Ré R. Informed consent for whole-genome sequencing studies in the clinical setting. Proposed recommendations on essential content and process. Eur J Hum Genet. 2013;21(10):1054–9.

    Article  PubMed  PubMed Central  Google Scholar 

  39. British Society for Genetic Medicine [Internet]. [Cited 2018 Oct 31]. http://www.bsgm.org.uk/.

  40. Ulm E, Feero WG, Dineen R, Charrow J, Wicklund C. Genetics professionals’ opinions of whole-genome sequencing in the newborn period. J Genet Couns. 2015;24(3):452–63.

    Article  PubMed  Google Scholar 

  41. Goldenberg AJ, Dodson DS, Davis MM, Tarini BA. Parents’ interest in whole-genome sequencing of newborns. Genet Med. 2014;16(1):78–84.

    Article  PubMed  Google Scholar 

  42. Hollegaard MV, Grauholm J, Nielsen R, Grove J, Mandrup S, Hougaard DM. Archived neonatal dried blood spot samples can be used for accurate whole genome and exome-targeted next-generation sequencing. Mol Genet Metab. 2013;110(1–2):65–72.

    Article  CAS  PubMed  Google Scholar 

  43. Poulsen JB, Lescai F, Grove J, Bækvad-Hansen M, Christiansen M, Hagen CM, et al. High-quality exome sequencing of whole-genome amplified neonatal dried blood spot DNA. PLoS One. 2016;11(4):e0153253.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  44. Boemer F, Fasquelle C, d’Otreppe S, Josse C, Dideberg V, Segers K, et al. A next-generation newborn screening pilot study: NGS on dried blood spots detects causal mutations in patients with inherited metabolic diseases. Sci Rep. 2017;7(1):17641.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Berg JS, Agrawal PB, Bailey DB, Beggs AH, Brenner SE, Brower AM, et al. Newborn sequencing in genomic medicine and public health. Pediatrics. 2017;139(2):e20162252.

    Article  PubMed  PubMed Central  Google Scholar 

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Author information

Authors and Affiliations

  1. Department of Paediatrics, Sherwood Forest Hospitals, Sutton-in-Ashfield, UK

    Richard Hastings

  2. Department of Clinical Genetics, Nottingham University Hospitals, Nottingham, UK

    Abhijit Dixit

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  1. Richard Hastings
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Correspondence to Abhijit Dixit .

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Editors and Affiliations

  1. Department of Health Sciences, George Davies Centre for Medicine, University of Leicester, Leicester, UK

    Elaine M. Boyle

  2. Department of Health Sciences, George Davies Centre for Medicine, University of Leicester, Leicester, UK

    Jonathan Cusack

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Hastings, R., Dixit, A. (2020). Genomics for the Neonatologist. In: Boyle, E., Cusack, J. (eds) Emerging Topics and Controversies in Neonatology. Springer, Cham. https://doi.org/10.1007/978-3-030-28829-7_32

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  • DOI: https://doi.org/10.1007/978-3-030-28829-7_32

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  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-030-28828-0

  • Online ISBN: 978-3-030-28829-7

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