The Genetics of Neonatal Surgical Conditions

  • Ian Ellis


It is noteworthy that in 1953, the same year that Peter Paul Rickham was establishing the first neonatal surgical unit at Alder Hey Children’s Hospital in Liverpool, just 200 miles away in Cambridge, Francis Crick and James Watson were unraveling the structure of DNA, the fundamental genetic material. Crick and Watson’s Nobel Prize winning work describing the double helix structure of DNA also described a mechanism for its replication. The two parent DNA strands each acting as the framework for copying into the two daughter strands. The usual accuracy of the copying of billions of base-pairs into gametes at meiosis and daughter cells during mitosis is itself a marvel. Changes in the usually faithful copying of DNA strands (mutations) can be the basis of positive genetic change that encourages our evolution over generations. Or the sudden deleterious change in a DNA sequence may be the pathogenic mutation that underlies a congenital malformation that presents to a neonatal surgeon. Here lies the origin of many neonatal surgical conditions and ultimately important clues to their improved management and ultimately their reduction or even prevention.


Human Genome Project (HGP) Gene Mutation Birth defect Malformation Clinical genetics Syndrome diagnosis Dysmorphology Mendelian Multifactorial Polygenic inheritance Recurrence risk Chromosome Fluorescent in situ hybridisation (FISH) Micro-array analysis DNA transcription factor Embryogenesis Hox SOX PAX genes Genotype Phenotype Gene expression Incomplete penetrance Variable expression Heritability Hirschprung disease (HSCR) Genome wide association study (GWAS) Single nucleotide polymorphism (SNP) Copy number variant (CNV) Unclassified variant (UCV) Epigenetic imprinting Anti-sense oligonucleotide RNA interference Gene silencing Next generation sequencing (NGS) Exome sequencing Whole genome sequencing (WGS) DECIPHER database Genetic counselling Family tree Pedigree Prenatal diagnosis Fetal ultrasound Chorionic villus sampling (CVS) Amniocentesis Cell free fetal DNA (cffDNA) Non-invasive prenatal diagnosis (NIPD) Pre-implantation genetic diagnosis (PGD) Termination of pregnancy Non-directive Non-judgmental counselling Support 


  1. 1.
    Watson JD, et al. Genetical implications of the structure of deoxyribonucleic acid. Nature. 1953;171:964–7.CrossRefGoogle Scholar
  2. 2.
    Collins FS, Morgan M, Patrinos A. The human genome project: lessons from large-scale biology. Science. 2003;300:286–90.CrossRefGoogle Scholar
  3. 3.
    Strachan T, Read A. Human molecular genetics (4th edition) Garland Science; 2010. ISBN 0815341490.Google Scholar
  4. 4.
    Watson JD, Baker TA, Bell SB, Gann A, Levine M, Losick R. Molecular Biology of the Gene (7th edition), Benjamin Cummings; 2013. ISBN 0321762436.Google Scholar
  5. 5.
    Molecular cell biology (Lodish, Molecular Cell Biology, 6th edition) Lodish H, Berk A, Kaiser CA, Krieger M, Scott MP, Bretscher A, Ploegh H, Matsudaira P (Authors), W H Freeman; 2008.Google Scholar
  6. 6.
    EUROCAT—The European registry of congenital anomalies.
  7. 7.
    World Health Programme, Human Genetics Programme.
  8. 8.
    Born Healthy Programme and Toolkits established by the Public Health Genetics Foundation.
  9. 9.
    Genetics & Dysmorphology by Tsai AC-H, Manchester DK, Elias ER, In: Current diagnosis and treatment pediatrics, 12th edition [NOOK Book] by Hay W, Levin M, Deterding R, Sondheimer J. McGraw-Hill Companies; 2010.–1053.pdf
  10. 10.
    Sadler TW. Langman’s medical embryology. 11th edition, Wolters Kluwer Health, Lippincott Williams &Wilkens. ISBN 0781743109.Google Scholar
  11. 11.
    Jongmans MC, Admiraal RJ, van der Donk KP, et al. CHARGE syndrome: the phenotypic spectrum of mutations in the CHD7 gene. J Med Genet. 2006;43:306–14.CrossRefGoogle Scholar
  12. 12.
    Website database of all published variants and unpublished variants for the CHD7 locus. www.CHD7.0rg.
  13. 13.
    Lalani SR, Safiullah AM, Fernbach SD, et al. Spectrum of CHD7 mutations in 110 Individuals with CHARGE syndrome and genotype-phenotype correlation. Am J Hum Genet. 2006;78:303–14.CrossRefGoogle Scholar
  14. 14.
    Janssen N, Bergman JE, Swertz MA, et al. Mutation. update on the CHD7 gene involved in CHARGE syndrome. Hum Mutat. 2012;Mar 27, Epub ahead of print.
  15. 15.
    Pearson JC, et al. Modulating Hox gene functions during animal body patterning. Nat Rev Genet. 2005;6:893–904.CrossRefGoogle Scholar
  16. 16.
    Winslow BB, et al. Global patterning of the vertebrate mesoderm. DevDyn. 2007;236:2371–81.Google Scholar
  17. 17.
    Alexander T, et al. Hox genes and segmentation of the hindbrain and axial skeleton. Annu Rev Cell Dev Biol. 2009;25:431–56.CrossRefGoogle Scholar
  18. 18.
    Wellik DM. Hox genes and vertebrae axial pattern. Curr Top Dev Biol. 2009;88:257–78.CrossRefGoogle Scholar
  19. 19.
    Mallo M, et al. Hox genes and regional patterning of the vertebrate body plan. Dev Biol. 2010;344(1):7–15. Epub 2010 May 7. Review.CrossRefGoogle Scholar
  20. 20.
    Goodman FR. Limb malformations and the human HOX genes. Am J Med Genet. 2002 Oct 15;112(3):256–65.CrossRefGoogle Scholar
  21. 21.
    Goodman FR, Scambler PJ. Human HOX gene mutations. Clin Genet. 2001 Jan;59(1):1–11.CrossRefGoogle Scholar
  22. 22.
    Nakano K, et al. Novel mutations of the HOXD13 gene in hand and foot malformations. Int Surg. 2007;92(5):287–95.Google Scholar
  23. 23.
    Lappin TR, et al. HOX genes: seductive science, mysterious mechanisms. Ulster Med J. 2006;75(1):23–31.PubMedPubMedCentralGoogle Scholar
  24. 24.
    Zhao X, et al. Mutations in HOXD13 underlie syndactyly type V and a novel brachydactyly-syndactyly syndrome. Am J Hum Genet. 2007;80(2):361–71.CrossRefGoogle Scholar
  25. 25.
    Gimelli S, Caridi G, Beri S, et al. Mutations in SOX17 are associated with congenital anomalies of the kidney and the urinary tract. Hum Mutat. 2010;31:1352–9.CrossRefGoogle Scholar
  26. 26.
    King M, Arnold JS, Shanske A, Morrow BE. T-genes and limb bud development. Am J Med Genet. 2006;140:1407–13.CrossRefGoogle Scholar
  27. 27.
    Hatcher CJ, Goldstein MM, Mah CS, et al. Identification and localization of TBX5 transcription factor during human cardiac morphogenesis. Dev Dyn. 2000;219(1):90–5.CrossRefGoogle Scholar
  28. 28.
    Packham EA, Brook JD. T-box genes in human disorders. Hum Mol Genet. 2003;12(1):R37–44.CrossRefGoogle Scholar
  29. 29.
    Mori AD, Bruneau BG. TBX5 mutations and congenital heart disease: Holt-Oram syndrome revealed. CurrOpin Cardi. 2004;19:211–5.CrossRefGoogle Scholar
  30. 30.
    Fisher RA. The correlation between relatives on the supposition of Mendelian inheritance. Trans Roy Soc Edinburgh. 1918;52:399–433.CrossRefGoogle Scholar
  31. 31.
    Falconer DS. A note on Fisher’s ‘average effect’ and ‘average excess’. Genet Res. 1985;46:337–47.CrossRefGoogle Scholar
  32. 32.
    Amiel J, Lyonnet S. Hirschprung disease, associated syndromes, and genetics: a review. J Med Genet. 2001;38:729–39.CrossRefGoogle Scholar
  33. 33.
    Parisi MA. Hirschprung disease overview. In: Pagon RA, Bird TD, Dolan CR, et al., editors. Gene Reviews [Internet]. University of Washington, Seattle; 2011.
  34. 34.
    Carter CO. Genetics of common disorders. Br Med Bull. 1969;25:52–7.CrossRefGoogle Scholar
  35. 35.
    Burzynski GM, Nolte IM, Bronda A, et al. Identifying candidate hirschsprung disease-associated RET variants. Am J Hum Genet. 2005;76(5):850–8.CrossRefGoogle Scholar
  36. 36.
    Manolio TA. Genomewide association studies and assessment of the risk of disease. N Engl J Med. 2010;363:166–76.CrossRefGoogle Scholar
  37. 37.
    Alves MM, Sribudiani Y, Brouwer RW, et al. Contribution of rare and common variants determine complex diseases-Hirschsprung disease as a model. Dev Biol. 2013;382(1):320–9.CrossRefGoogle Scholar
  38. 38.
    Allanson JE, Cunniff C, Hoyme HE, et al. Elements of morphology: standard terminology for the head and face. Am J Med Genet. 2009;149A:6–28.CrossRefGoogle Scholar
  39. 39.
    OMIM, Online Mendelian Inheritance in Man -a comprehensive compendium of human genes and genetic phenotypes.
  40. 40.
    Gene Reviews. In: Pagon RA editor, Bird TD, Dolan CR, Stephens K, Adam MP editor-in-chief. Seattle (WA): University of Washington, Seattle; 1993.
  41. 41.
    GeneTests—a publicly funded medical genetics information resource providing current, authoritative information on genetic testing and its use in diagnosis, management, and genetic counseling.
  42. 42.
    Aase JM. Diagnostic dysmorphology, Springer; 1990. ISBN 030643444X.Google Scholar
  43. 43.
    Jones KL. Smith’s recognizable patterns of human malformation (6th edition). Saunders, London; 2006.Google Scholar
  44. 44.
    Reardon W. The Bedside dysmorphologist. Oxford University Press; 2007. ISBN: 0195300459.Google Scholar
  45. 45.
    Hennekam R, Allanson J, Krantz I. Gorlin’s syndromes of the head and neck (Oxford Monographs on Medical Genetics, 5th edition). Oxford University Press; 2010.Google Scholar
  46. 46.
    Gardner RJ, Sutherland GR, Shaffer LG. Chromosome abnormalities and genetic counseling (Oxford Monographs on Medical Genetics No. 61, 4th edition), Oxford University Press; 2012. ISBN 0195375335.Google Scholar
  47. 47.
    Shaffer LG. American College of Medical Genetics Professional Practice and Guidelines Committee. American College of Medical Genetics guideline on the cytogenetic evaluation of the individual with developmental delay or mental retardation. Genet Med. 2005;7:650–4.CrossRefGoogle Scholar
  48. 48.
    Knight SJ, Flint J. Review. Perfect endings: a review of subtelomeric probes and their use in clinical diagnosis. J Med Genet. 2000 Jun;37:401–9.CrossRefGoogle Scholar
  49. 49.
    de Vries BB, White SM, Knight SJ, Regan R, et al. Clinical studies on submicroscopicsubtelomeric rearrangements: a checklist. J Med Genet. 2001;38:145–50.CrossRefGoogle Scholar
  50. 50.
    deVries BB, Winter R, Schinzel A, et al. Telomeres: a diagnosis at the end of the chromosomes. J Med Genet. 2003;40:385–98.CrossRefGoogle Scholar
  51. 51.
    Vermeesch JR, Fiegler H, de Leeuw N, et al. Guidelines for molecular karyotyping in constitutional genetic diagnosis. Eur J Hum Genet. 2007;15:1105–14.CrossRefGoogle Scholar
  52. 52.
    Brady PD, Vermeesch JR. Genomic microarrays: a technology overview. Prenat Diagn. 2012;32:336–43.CrossRefGoogle Scholar
  53. 53.
    Deciphering Developmental Disorders (DDD), Research Study, Wellcome Trust Sanger Institute, Hinxton, Cambs, CB10 1SA, UK.
  54. 54.
    Stankiewicz P, Beaudet AL. Use of array CGH in the evaluation of dysmorphology, malformations, developmental delay, and idiopathic mental retardation. Curr Opin Genet Dev. 2007;17:182–92.CrossRefGoogle Scholar
  55. 55.
    Lu XY, Phung MT, Shaw CA, et al. Genomic imbalances in neonates with birth defects: high detection rates by using chromosomal microarray analysis. Pediatrics. 2008;122:1310–8.CrossRefGoogle Scholar
  56. 56.
    Determination of nucleotide sequences in DNA. Nobel Prize lecture, 8 December 1980 by Frederick Sanger, MRC Laboratory of Molecular Biology, Cambridge, England.
  57. 57.
    Gerdes T, Kirchoff M, Lind AM, et al. Computer-assisted prenatal aneuploidy screening for chromosome 13, 18, 21, X and Y based on multiplex ligation-dependent probe amplification (MLPA). Eur J Hum Genet. 2005;13:171–5.CrossRefGoogle Scholar
  58. 58.
    Brenner S, et al. Gene expression analysis by massively parallel signature sequencing (MPSS) on microbead arrays. Nat Biotechnol. 2000;18:630–4.CrossRefGoogle Scholar
  59. 59.
    The Sanger Centre DECIPHER database. DECIPHER: Database of Chromosomal Imbalance and Phenotype in Humans using Ensembl Resources. Firth HV, et al. Am J Hum Genet. 2009;84:524–33. doi:, CrossRefGoogle Scholar
  60. 60.
    Barbaro M, Wedell A, Nordenström A. Disorders of sex development. Semin Fetal Neonatal Med. 2011;16:119–27.CrossRefGoogle Scholar
  61. 61.
    Paris F, Gaspari L, Philibert P, et al. Disorders of sex development: neonatal diagnosis and management. Endocr Dev. 2012;22:56–71.CrossRefGoogle Scholar
  62. 62.
    Resta R, Biesecker BB, Bennett RL et al. A new definition of genetic counseling: National Society of Genetic Counselors’ Task Force Report. 2006;15:77–83.Google Scholar
  63. 63.
    The Genomics Education Programme (GEP) of the NHS.
  64. 64.
    McConkey EH. How the genome works. Jones and Bartlett Publishers, Sudbury, MA; 2004. ISBN 0–7636–2384–3.Google Scholar
  65. 65.
    Oxford Desk Reference: Clinical genetics: HV Firth, JA Hurst. Oxford: Oxford University Press; 2005. ISBN 0–19–262896–8.Google Scholar
  66. 66.
    Harper P. Practical genetic counseling.7th edition. Hodder Arnold Publication; 2010. ISBN 10:0340990694.Google Scholar
  67. 67.
    Skirton H, Barnes C, Guilbert P, et al. Clinical practice in medical genetics recommendations for education and training of genetic nurses and counsellors in the United Kingdom. J Med Genet. 1998;35:410–2.–0058.pdf.CrossRefGoogle Scholar
  68. 68.
    Kan YW, Chang JC, Dozy AM. Prenatal diagnosis by DNA analysis. Birth Defects Orig Artic Ser. 1982;18:275–83.Google Scholar
  69. 69.
    Wright CF, Burton H. The use of cell-free fetal nucleic acids in maternal blood for non-invasive prenatal daiganosis. Hum Reprod Update. 2009;15:139–51.CrossRefGoogle Scholar
  70. 70.
    Lewis C, Hill M, Skirton H, Chitty LS. Non-invasive prenatal diagnosis forfetal sex determination: benefits and disadvantages from the service users’ perspective. Eur J Hum Genet. 2012;20:1127–33.CrossRefGoogle Scholar
  71. 71.
    Wright C. Cell-free fetal nucleic acids for non-invasive prenatal diagnosis. Report of the UK expert working group. Public Health Genetics Foundation; 2009.Google Scholar
  72. 72.
    The Wellcome Trust, The human genome—Genetic counselling.
  73. 73.
    The World Health Organization. Human Genetics programme. Ethical, legal and social implications (ELSI) of human genomics.
  74. 74.
    Yarborough M, Scott JA. Dixon LK The role of beneficence in clinical genetics: non-directive counselling reconsidered. Theor Med. 1989;10:139–49.CrossRefGoogle Scholar
  75. 75.
    Chervenak FA, McCullough LB. The fetus as a patient: an essential ethical concept of maternal-fetal medicine. J Matern Fetal Med. 1996;5:115–9.Google Scholar
  76. 76.
    Kessler S. Psychological aspects of genetic counseling. XI. Nondirectiveness revisted. Am J Med Genet. 1997;72:164–71.CrossRefGoogle Scholar
  77. 77.
    Orphanet—the portal for rare diseases and rare drugs.

Copyright information

© Springer-Verlag London Ltd., part of Springer Nature 2018

Authors and Affiliations

  1. 1.Department of Clinical GeneticsLiverpool Women’s HospitalLiverpoolUK

Personalised recommendations