Update in Clinical Genetics and Metabolics

Chapter

Abstract

Clinical genetics has undergone unprecedented change in recent years. The increasing sophistication of genetic testing and the accelerating tempo of disease gene discovery are greatly improving rates of successful clinical diagnosis for many patients. New, powerful techniques such as whole-exome sequencing have made it possible to identify all or most of the protein-coding genetic variants in an individual. At the same time, a great deal has been learned about the clinical spectra of many genetic syndromes; in particular, the mild or non-classical presentations of many disorders are becoming increasingly recognized. The field of metabolics has seen rapid progress due to the adoption in many industrialized countries of mass-spectrometry-based expanded newborn screening. The roles of hematopoietic stem cell and solid organ transplantation in the treatment of metabolic disorders continue to expand. The role of gene therapy, which is currently available for selected disorders, continues to expand, and is likely to play an increasingly prominent role in the future.

Keywords

Chromosomal microarray Syndrome Whole exome sequencing Next generation sequencing Autism/developmental delay/intellectual disability Congenital anomalies Inborn errors of metabolism Newborn screening Enzyme replacement therapy Hematopoietic stem cell transplantation/solid organ transplantation 

References

  1. 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.CrossRefGoogle Scholar
  2. American Academy of Pediatrics Committee on Genetics. Health care supervision for children with Williams syndrome. Pediatrics. 2001;107(5):1192–204. Erratum in: Pediatrics 2002;109(2):329Google Scholar
  3. American College of Medical Geneticists. ACMG ACT sheets and confirmatory algorithms [Internet]. Bethesda, MD: ACMG; 2001. http://www.ncbi.nlm.nih.gov/books/NBK55827/. Accessed 11 Nov 2016Google Scholar
  4. Andermann A, Blancquaert I, Beauchamp S, Déry V. Revisiting Wilson and Jungner in the genomic age: a review of screening criteria over the past 40 years. Bull World Health Organ. 2008;86(4):317–9.CrossRefGoogle Scholar
  5. Aoki Y, Niihori T, Inoue S, Matsubara Y. Recent advances in RASopathies. J Hum Genet. 2016;61(1):33–9.CrossRefGoogle Scholar
  6. Boelens JJ, Aldenhoven M, Purtill D, Ruggeri A, Defor T, Wynn R, et al. Outcomes of transplantation using various hematopoietic cell sources in children with Hurler syndrome after myeloablative conditioning. Blood. 2013;121(19):3981–7.CrossRefGoogle Scholar
  7. Boone PM, Soens ZT, Campbell IM, Stankiewicz P, Cheung SW, Patel A, Beaudet AL, Plon SE, Shaw CA, McGuire AL, Lupski JR. Incidental copy-number variants identified by routine genome testing in a clinical population. Genet Med. 2013;15(1):45–54.CrossRefGoogle Scholar
  8. Boycott K, Hartley T, Adam S, Bernier F, Chong K, Fernandez BA, Friedman JM, Geraghty MT, Hume S, Knoppers BM, Laberge AM, Majewski J, Mendoza-Londono R, Meyn MS, Michaud JL, Nelson TN, Richer J, Sadikovic B, Skidmore DL, Stockley T, Taylor S, van Karnebeek C, Zawati MH, Lauzon J, Armour CM, Canadian College of Medical Geneticists. The clinical application of genome-wide sequencing for monogenic diseases in Canada: position statement of the Canadian College of Medical Geneticists. J Med Genet. 2015;52(7):431–7.CrossRefGoogle Scholar
  9. Calvo SE, Compton AG, Hershman SG, Lim SC, Lieber DS, Tucker EJ, et al. Molecular diagnosis of infantile mitochondrial disease with targeted next-generation sequencing. Sci Transl Med. 2012;4(118):118ra10.CrossRefGoogle Scholar
  10. Charrow J, Goodman SI, McCabe ERG, Rinaldo P. (American College of Medical Genetics/American Society of Human Genetics Test and Technology Transfer Committee Working Group). Tandem mass spectrometry in newborn screening. Genet Med. 2000;2(4):267–9.CrossRefGoogle Scholar
  11. Clarke JTR. A clinical guide to inherited metabolic diseases. 3rd ed. New York, NY: Cambridge University Press; 2006.Google Scholar
  12. Cooper GM, Shendure J. Needles in stacks of needles: finding disease-causal variants in a wealth of genomic data. Review Nat Rev Genet. 2011;12(9):628–40.CrossRefGoogle Scholar
  13. Davis RL, Liang C, Sue CM. A comparison of current serum biomarkers as diagnostic indicators of mitochondrial diseases. Neurology. 2016;86(21):2010–5.CrossRefGoogle Scholar
  14. Editorial. Gene-therapy trials must proceed with caution. Nature. 2016;534(7609):590.CrossRefGoogle Scholar
  15. van El CG, Cornel MC, Borry P, Hastings RJ, Fellmann F, Hodgson SV, Howard HC, Cambon-Thomsen A, Knoppers BM, Meijers-Heijboer H, Scheffer H, Tranebjaerg L, Dondorp W, de Wert GM, Public Professional Policy Committee ESHG. Whole-genome sequencing in health care: recommendations of the European Society of Human Genetics. EJHG. 2013;21:580–4.PubMedPubMedCentralGoogle Scholar
  16. Elliott S, Buroker N, Cournoyer JJ, Potier AM, Trometer JD, Elbin C, et al. Pilot study of newborn screening for six lysosomal storage diseases using Tandem Mass Spectrometry. Mol Genet Metab. 2016;118(4):304–9.CrossRefGoogle Scholar
  17. Ezkurdia I, Juan D, Rodriguez JM, Frankish A, Diekhans M, Harrow J, Vazquez J, Valencia A, Tress ML. Multiple evidence strands suggest that there may be as few as 19,000 human protein-coding genes. Hum Mol Genet. 2014;23(22):5866–78.CrossRefGoogle Scholar
  18. Fratantoni JC, Hall CW, Neufeld EF. Hurler and Hunter syndromes: mutual correction of the defect in cultured fibroblasts. Science. 1968;162(3853):570–2.CrossRefGoogle Scholar
  19. Gaspar HB. Gene therapy for ADA-SCID: defining the factors for successful outcome. Blood. 2012;120(18):3628–9.CrossRefGoogle Scholar
  20. Ginn SL, Alexander IE, Edelstein ML, Abedi MR, Wixon J. Gene therapy clinical trials worldwide to 2012- an update. J Gen Med 2013;15(2):65–77Google Scholar
  21. Green RC, Berg JS, Grody WW, Kalia SS, Korf BR, Martin CL, McGuire AL, Nussbaum RL, O’Daniel JM, Ormond KE, Rehm HL, Watson MS, Williams MS, Biesecker LG, American College of Medical Genetics and Genomics. ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med. 2013;15:565–74.CrossRefGoogle Scholar
  22. Hersh JH, Saul RA, Committee on Genetics. Health supervision for children with fragile X syndrome. Pediatrics. 2011;127(5):994–1006.CrossRefGoogle Scholar
  23. Hoggatt J. Gene therapy for "Bubble Boy" disease. Cell. 2016;166(2):263.CrossRefGoogle Scholar
  24. International Human Genome Sequencing Consortium. Finishing the euchromatic sequence of the human genome. Nature. 2004;431(7011):931–45.CrossRefGoogle Scholar
  25. van Karnebeek CD, Stockler-Ipsiroglu S. Early identification of treatable inborn errors of metabolism in children with intellectual disability: the treatable intellectual disability endeavor protocol in British Columbia. Paediatr Child Health. 2014;19(9):469–71.CrossRefGoogle Scholar
  26. Kingswood JC, Bissler JJ, Budde K, Hulbert J, Guay-Woodford L, Sampson JR, Sauter M, Cox J, Patel U, Elmslie F, Anderson C, Zonnenberg BA. Review of the tuberous sclerosis renal guidelines from the 2012 consensus conference: current data and future study. Nephron. 2016;134(2):51–8.CrossRefGoogle Scholar
  27. Lacro RV, Dietz HC, Sleeper LA, Yetman AT, Bradley TJ, Colan SD, Pearson GD, Selamet Tierney ES, Levine JC, Atz AM, Benson DW, Braverman AC, Chen S, De Backer J, Gelb BD, Grossfeld PD, Klein GL, Lai WW, Liou A, Loeys BL, Markham LW, Olson AK, Paridon SM, Pemberton VL, Pierpont ME, Pyeritz RE, Radojewski E, Roman MJ, Sharkey AM, Stylianou MP, Wechsler SB, Young LT, Mahony L, Pediatric Heart Network Investigators. Atenolol versus losartan in children and young adults with Marfan’s syndrome. N Engl J Med. 2014;371(22):2061–71.CrossRefGoogle Scholar
  28. Lee H, Deignan JL, Dorrani N, et al. Clinical exome sequencing for genetic identification of rare Mendelian disorders. JAMA. 2014;312:1880–7.CrossRefGoogle Scholar
  29. Lieber DS, Calvo SE, Shanahan K, Slate NG, Liu S, Hershman SG, et al. Targeted exome sequencing of suspected mitochondrial disorders. Neurology. 2013;80(19):1762–70.CrossRefGoogle Scholar
  30. Matern D, Starzl TE, Arnaout W, Barnard J, Bynon JS, Dhawan A, Emond J, Haagsma EB, Hug G, Lachaux A, Smit GP, Chen YT. Liver transplantation for glycogen storage disease types I, III, and IV. Review. Eur J Pediatr. 1999;158(Suppl 2):S43–8.CrossRefGoogle Scholar
  31. Michelson DJ, Shevell MI, Sherr EH, Moeschler JB, Gropman AL, Ashwal S. Evidence report: genetic and metabolic testing on children with global developmental delay: report of the Quality Standards Subcommittee of the American Academy of Neurology and the Practice Committee of the Child Neurology Society. Neurology. 2011;77(17):1629–35.CrossRefGoogle Scholar
  32. Miller DT, Adam MP, Aradhya S, Biesecker LG, Brothman AR, Carter NP, Church DM, Crolla JA, Eichler EE, Epstein CJ, Faucett WA, Feuk L, Friedman JM, Hamosh A, Jackson L, Kaminsky EB, Kok K, Krantz ID, Kuhn RM, Lee C, Ostell JM, Rosenberg C, Scherer SW, Spinner NB, Stavropoulos DJ, Tepperberg JH, Thorland EC, Vermeesch JR, Waggoner DJ, Watson MS, Martin CL, Ledbetter DH. Consensus statement: chromosomal microarray is a first-tier clinical diagnostic test for individuals with developmental disabilities or congenital anomalies. Am J Hum Genet. 2010;86(5):749–64.CrossRefGoogle Scholar
  33. Miller MJ, Kennedy AD, Eckhart AD, Burrage LC, Wulff JE, Miller LA, et al. Untargeted metabolomics analysis for the clinical screening of inborn errors of metabolism. J Inherit Metab Dis. 2015;38(6):1029–39.CrossRefGoogle Scholar
  34. Moeschler JB, Shevell M, Committee on Genetics. Comprehensive evaluation of the child with intellectual disability or global developmental delays. Pediatrics. 2014;134(3):e903–18.CrossRefGoogle Scholar
  35. Niemi AK, Kim IK, Krueger CE, Cowan TM, Baugh N, Farrell R, et al. Treatment of methylmalonic acidemia by liver or combined liver-kidney transplantation. J Pediatr. 2015;166(6):1455–61.e1.CrossRefGoogle Scholar
  36. Nyhan WL, Hoffman GF, Barshop BA, Al-Aqeel AI. Atlas of inherited metabolic diseases. 3rd ed. London: Hodder Arnold; 2012.Google Scholar
  37. OMIM. Online Mendelian inheritance in man, OMIM®. Baltimore, MD: McKusick-Nathans Institute of Genetic Medicine, Johns Hopkins University; 2016. http://omim.org/Google Scholar
  38. Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, LJH B, et al., editors. GeneReviews [Internet]. Seattle, WA: University of Washington, Seattle; 1993. http://www.ncbi.nlm.nih.gov/books/NBK1116/. Accessed 9 Nov 2016Google Scholar
  39. Pichert G, Mohammed SN, Ahn JW, Ogilvie CM, Izatt L. Unexpected findings in cancer predisposition genes detected by array comparative genomic hybridisation: what are the issues? J Med Genet. 2011;48(8):535–9.CrossRefGoogle Scholar
  40. Platt FM, Jeyakumar M. Substrate reduction therapy. Review. Acta Paediatr. 2008;97(457):88–93.CrossRefGoogle Scholar
  41. Popescu I, Dima SO. Domino liver transplantation: how far can we push the paradigm? Review. Liver Transpl. 2012;18(1):22–8.  https://doi.org/10.1002/lt.22443.CrossRefPubMedGoogle Scholar
  42. Retterer K, Juusola J, Cho MT, Vitazka P, Millan F, Gibellini F, Vertino-Bell A, Smaoui N, Neidich J, Monaghan KG, McKnight D, Bai R, Suchy S, Friedman B, Tahiliani J, Pineda-Alvarez D, Richard G, Brandt T, Haverfield E, Chung WK, Bale S. Clinical application of whole-exome sequencing across clinical indications. Genet Med. 2016;18(7):696–704.CrossRefGoogle Scholar
  43. Saudubray JM, Baumgartner MR, Walter J, editors. Inborn metabolic diseases: diagnosis and treatment. 6th ed. Heidelberg: Springer-Verlag; 2016.Google Scholar
  44. Shamseldin HE, Tulbah M, Kurdi W, Nemer M, Alsahan N, Al Mardawi E, et al. Identification of embryonic lethal genes in humans by autozygosity mapping and exome sequencing in consanguineous families. Genome Biol. 2015;16:116.CrossRefGoogle Scholar
  45. Sims D, Sudbery I, Ilott NE, Heger A, Ponting CP. Sequencing depth and coverage: key considerations in genomic analyses. Nat Rev Genet. 2014;15(2):121–32.CrossRefGoogle Scholar
  46. Somaraju UR, Merrin M. Sapropterin dihydrochloride for phenylketonuria. Cochrane Database Syst Rev. 2015;3:CD008005.Google Scholar
  47. Sparks SE, Krasnewich DM. Congenital disorders of N-linked glycosylation pathway overview. In: Pagon RA, Adam MP, Ardinger HH, Wallace SE, Amemiya A, LJH B, et al., editors. GeneReviews® [Internet]. Seattle, WA: University of Washington, Seattle; 2005. http://www.ncbi.nlm.nih.gov/books/NBK1332/.Google Scholar
  48. U. S. Department of Health and Human Services Advisory Committee on Heritable Disorders in Newborns and Children. Recommended Uniform Screening Panel 2015. http://www.hrsa.gov/advisorycommittees/mchbadvisory/heritabledisorders/recommendedpanel/. Accessed on 10 Nov 2016.
  49. Vafai SB, Mootha VK. Mitochondrial disorders as windows into an ancient organelle. Rev Nat. 2012;491(7424):374–83.Google Scholar
  50. Valle D, Beaudet AL, Vogelstein B, Kinzler KW, Antonarakis SE, Ballabio A, et al., editors. The online metabolic and molecular bases of inherited disease [Internet]. New York, NY: McGraw-Hill Medical; 2016. http://ommbid.mhmedical.com/ommbid-index.aspx (with authorized username and password). Accessed 9 Nov 2016Google Scholar
  51. Ward P, Walsh CE. Current and future prospects for hemophilia gene therapy. Expert Rev Hematol. 2016;9(7):649–59.CrossRefGoogle Scholar
  52. Wasserstein MP, Andriola M, Arnold G, Aron A, Duffner P, Erbe RW, et al. Clinical outcomes of children with abnormal newborn screening results for Krabbe disease in New York State. Genet Med. 2016;18(12):1235–43.  https://doi.org/10.1038/gim.2016.35.CrossRefPubMedGoogle Scholar
  53. Wilson JMG, Jungner G. Principles and practice of screening for disease. Geneva: WHO; 1968. http://www.who.int/bulletin/volumes/86/4/07-050112BP.pdfGoogle Scholar
  54. Yang Y, Muzny DM, Xia F, et al. Molecular findings among patients referred for clinical whole-exome sequencing. JAMA. 2014;312:1870–9.CrossRefGoogle Scholar
  55. Yu L, Rayhill SC, Hsu EK, Landis CS. Liver transplantation for urea cycle disorders: analysis of the United Network for Organ Sharing Database. Transplant Proc. 2015;47(8):2413–8.CrossRefGoogle Scholar
  56. Zschocke J, Hoffmann GF. Vademecum metabolicum. 3rd ed. Friedrichsdorf: Milupa Metabolics GmbH; 2011. http://evm.health2media.com/#/start Google Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2018

Authors and Affiliations

  1. 1.Regional Genetics UnitChildren’s Hospital of Eastern OntarioOttawaCanada
  2. 2.Metabolics, Department of PediatricsChildren’s Hospital of Eastern OntarioOttawaCanada

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