Skip to main content

Advertisement

SpringerLink
Log in

Clinical genomics: from a truly personal genome viewpoint

  • Perspective
  • Published:
Human Genetics Aims and scope Submit manuscript

Abstract

The path to Clinical Genomics is punctuated by our understanding of what types of DNA structural and sequence variation contribute to disease, the many technical challenges to detect such variation genome-wide, and the initial struggles to interpret personal genome variation in the context of disease. This review describes one perspective of the development of clinical genomics; whereas the experimental challenges, and hurdles to overcoming them, might be deemed readily apparent, the non-technical issues for clinical implementation may be less obvious. Some of these latter challenges, including: (1) informed consent, (2) privacy, (3) what constitutes potentially pathogenic variation contributing to disease, (4) disease penetrance in populations, and (5) the genetic architecture of disease, and the struggles sometimes faced for solutions, are highlighted using illustrative examples.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4

Similar content being viewed by others

References

  • Albert TJ, Molla MN, Muzny DM, Nazareth L, Wheeler D, Song X et al (2007) Direct selection of human genomic loci by microarray hybridization. Nat Methods 4:903–905

    Article  CAS  PubMed  Google Scholar 

  • Bainbridge MN, Wang M, Burgess DL, Kovar C, Rodesch MJ, D’Ascenzo M et al (2010) Whole exome capture in solution with 3 Gbp of data. Genome Biol 11:R62

    Article  PubMed  PubMed Central  Google Scholar 

  • Bainbridge MN, Wiszniewski W, Murdock DR, Friedman J, Gonzaga-Jauregui C, Newsham I et al (2011a) Whole-genome sequencing for optimized patient management. Sci Transl Med 3:87re83

    Article  Google Scholar 

  • Bainbridge MN, Wang M, Wu Y, Newsham I, Muzny DM, Jefferies JL et al (2011b) Targeted enrichment beyond the consensus coding DNA sequence exome reveals exons with higher variant densities. Genome Biol 12:R68

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ballif BC, Rorem EA, Sundin K, Lincicum M, Gaskin S, Coppinger J et al (2006) Detection of low-level mosaicism by array CGH in routine diagnostic specimens. Am J Med Genet A. 140:2757–2767

    Article  PubMed  Google Scholar 

  • Bejjani BA, Saleki R, Ballif BC, Rorem EA, Sundin K, Theisen A et al (2005) Use of targeted array-based CGH for the clinical diagnosis of chromosomal imbalance: is less more? Am J Med Genet A 134:259–267

    Article  PubMed  Google Scholar 

  • Boone PM, Bacino CA, Shaw CA, Eng PA, Hixson PM, Pursley AN et al (2010) Detection of clinically relevant exonic copy-number changes by array CGH. Hum Mutat 31:1326–1342

    Article  PubMed  PubMed Central  Google Scholar 

  • Boone PM, Soens ZT, Campbell IM, Stankiewicz P, Cheung SW, Patel A et al (2013a) Incidental copy-number variants identified by routine genome testing in a clinical population. Genet Med. 15:45–54

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Boone PM, Campbell IM, Baggett BC, Soens ZT, Rao MM, Hixson PM et al (2013b) Deletions of recessive disease genes: CNV contribution to carrier states and disease-causing alleles. Genome Res 23:1383–1394

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Campbell IM, Yuan B, Robberecht C, Pfundt R, Szafranski P, McEntagart ME et al (2014a) Parental somatic mosaicism is underrecognized and influences recurrence risk of genomic disorders. Am J Hum Genet 95:173–182

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Campbell IM, Stewart JR, James RA, Lupski JR, Stankiewicz P, Olofsson P et al (2014b) Parent of origin, mosaicism, and recurrence risk: probabilistic modeling explains the broken symmetry of transmission genetics. Am J Hum Genet 95:345–359

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Campbell IM, Shaw CA, Stankiewicz P, Lupski JR (2015) Somatic mosaicism: implications for disease and transmission genetics. Trends Genet 31:382–392

    Article  CAS  PubMed  Google Scholar 

  • Carvalho CM, Lupski JR (2016) Mechanisms underlying structural variant formation in genomic disorders. Nat Rev Genet 17:224–238

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carvalho CM, Pfundt R, King DA, Lindsay SJ, Zuccherato LW, Macville MV et al (2015) Absence of heterozygosity due to template switching during replicative rearrangements. Am J Hum Genet 96:555–564

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Cheung SW, Shaw CA, Yu W, Li J, Ou Z, Patel A et al (2005) Development and validation of a CGH microarray for clinical cytogenetic diagnosis. Genet Med 7:422–432

    Article  PubMed  Google Scholar 

  • Cheung SW, Shaw CA, Scott DA, Patel A, Sahoo T, Bacino CA et al (2007) Microarray-based CGH detects chromosomal mosaicism not revealed by conventional cytogenetics. Am J Med Genet A. 143A:1679–1686

    Article  PubMed  Google Scholar 

  • Chong JX, Buckingham KJ, Jhangiani SN, Boehm C, Sobreira N, Smith JD et al (2015) The genetic basis of mendelian phenotypes: discoveries, challenges, and opportunities. Am J Hum Genet 97:199–215

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Daly AF, Yuan B, Fina F, Caberg JH, Trivellin G, Rostomyan L et al (2016) Somatic mosaicism underlies X-linked acrogigantism syndrome in sporadic male subjects. Endocr Relat Cancer 23:221–233

    Article  PubMed  Google Scholar 

  • English AC, Salerno WJ, Hampton OA, Gonzaga-Jauregui C, Ambreth S, Ritter DI et al (2015) Assessing structural variation in a personal genome-towards a human reference diploid genome. BMC Genom 16:286

    Article  Google Scholar 

  • Gambin T, Jhangiani SN, Below JE, Campbell IM, Wiszniewski W, Muzny DM et al (2015) Secondary findings and carrier test frequencies in a large multiethnic sample. Genome Med. 7:54

    Article  PubMed  PubMed Central  Google Scholar 

  • Gonzaga-Jauregui C, Lupski JR, Gibbs RA (2012) Human genome sequencing in health and disease. Annu Rev Med 63:35–61

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gonzaga-Jauregui C, Harel T, Gambin T, Kousi M, Griffin LB, Francescatto L et al (2015) Exome sequence analysis suggests that genetic burden contributes to phenotypic variability and complex neuropathy. Cell Rep. 12:1169–1183

    Article  CAS  PubMed  Google Scholar 

  • Green RC, Lupski JR, Biesecker LG (2013a) Reporting genomic sequencing results to ordering clinicians: incidental, but not exceptional. JAMA 310:365–366

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Green RC, Berg JS, Grody WW, Kalia SS, Korf BR, Martin CL et al (2013b) ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. Genet Med. 15:565–574

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hildebrandt G, Holler E, Woenkhaus M, Quarch G, Reichle A, Schalke B et al (2000) Acute deterioration of Charcot–Marie–Tooth disease IA (CMT IA) following 2 mg of vincristine chemotherapy. Ann Oncol 11:743–747

    Article  CAS  PubMed  Google Scholar 

  • International Human Genome Sequencing C (2004) Finishing the euchromatic sequence of the human genome. Nature 431:931–945

    Article  Google Scholar 

  • Karaca E, Harel T, Pehlivan D, Jhangiani SN, Gambin T, Coban Akdemir Z et al (2015) Genes that affect brain structure and function identified by rare variant analyses of Mendelian neurologic disease. Neuron 88:499–513

    Article  CAS  PubMed  Google Scholar 

  • Klitzman R, Appelbaum PS, Chung W (2013) Return of secondary genomic findings vs patient autonomy: implications for medical care. JAMA 310:369–370

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kremer LS, Distelmaier F, Alhaddad B, Hempel M, Iuso A, Kupper C et al (2016) Bi-allelic truncating mutations in TANGO2 cause infancy-onset recurrent metabolic crises with encephalocardiomyopathy. Am J Hum Genet 98:358–362

    Article  CAS  PubMed  Google Scholar 

  • Lalani SR, Liu P, Rosenfeld JA, Watkin LB, Chiang T, Leduc MS et al (2016) Recurrent muscle weakness with rhabdomyolysis, metabolic crises, and cardiac arrhythmia due to bi-allelic TANGO2 mutations. Am J Hum Genet 98:347–357

    Article  CAS  PubMed  Google Scholar 

  • Lander ES, Linton LM, Birren B, Nusbaum C, Zody MC, Baldwin J et al (2001) Initial sequencing and analysis of the human genome. Nature 409:860–921

    Article  CAS  PubMed  Google Scholar 

  • Lee H, Deignan JL, Dorrani N, Strom SP, Kantarci S, Quintero-Rivera F et al (2014) Clinical exome sequencing for genetic identification of rare Mendelian disorders. JAMA 312:1880–1887

    Article  PubMed  PubMed Central  Google Scholar 

  • Lemmers RJ, Tawil R, Petek LM, Balog J, Block GJ, Santen GW et al (2012) Digenic inheritance of an SMCHD1 mutation and an FSHD-permissive D4Z4 allele causes facioscapulohumeral muscular dystrophy type 2. Nat Genet 44:1370–1374

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lifton RP (2010) Individual genomes on the horizon. N Engl J Med 362:1235–1236

    Article  CAS  PubMed  Google Scholar 

  • Liu P, Erez A, Nagamani SC, Dhar SU, Kolodziejska KE, Dharmadhikari AV et al (2011) Chromosome catastrophes involve replication mechanisms generating complex genomic rearrangements. Cell 146:889–903

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lupski JR (2009) Genomic disorders ten years on. Genome Med 1:42

    Article  PubMed  PubMed Central  Google Scholar 

  • Lupski JR (2012) Digenic inheritance and Mendelian disease. Nat Genet 44:1291–1292

    Article  CAS  PubMed  Google Scholar 

  • Lupski JR (2015) Structural variation mutagenesis of the human genome: impact on disease and evolution. Environ Mol Mutagen 56:419–436

    Article  CAS  Google Scholar 

  • Lupski JR, Timmerman V (2006) The CMT1A duplication—a historical perspective viewed from two sides of an ocean. In: Lupski JR, Stankiewicz P (eds) Genomic disorders: the genomic basis of disease, Chapter 1. Humana Press Inc, Totowa, pp 3–17

    Chapter  Google Scholar 

  • Lupski JR, Reid JG, Gonzaga-Jauregui C, Rio Deiros D, Chen DC, Nazareth L et al (2010) Whole-genome sequencing in a patient with Charcot–Marie–Tooth neuropathy. N Engl J Med 362:1181–1191

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lupski JR, Belmont JW, Boerwinkle E, Gibbs RA (2011) Clan genomics and the complex architecture of human disease. Cell 147:32–43

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lupski JR, Gonzaga-Jauregui C, Yang Y, Bainbridge MN, Jhangiani S, Buhay CJ et al (2013) Exome sequencing resolves apparent incidental findings and reveals further complexity of SH3TC2 variant alleles causing Charcot–Marie–Tooth neuropathy. Genome Med. 5:57

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Maher CA, Wilson RK (2012) Chromothripsis and human disease: piecing together the shattering process. Cell 148:29–32

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Margulies M, Egholm M, Altman WE, Attiya S, Bader JS, Bemben LA et al (2005) Genome sequencing in microfabricated high-density picolitre reactors. Nature 437:376–380

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mirzaa GM, Campbell CD, Solovieff N, Goold CP, Jansen LA, Menon S, Timms AE et al (2016) Association of MTOR mutations with developmental brain disorders, including megalencephaly, focal cortical dysplasia, and pigmentary mosaicism. JAMA Neurol. doi:10.1001/jamaneurol.2016.0363

    PubMed  Google Scholar 

  • Nakamura T, Hashiguchi A, Suzuki S, Uozumi K, Tokunaga S, Takashima H (2012) Vincristine exacerbates asymptomatic Charcot–Marie–tooth disease with a novel EGR2 mutation. Neurogenetics. 13:77–82

    Article  CAS  PubMed  Google Scholar 

  • Pham J, Shaw C, Pursley A, Hixson P, Sampath S, Roney E et al (2014) Somatic mosaicism detected by exon-targeted, high-resolution aCGH in 10,362 consecutive cases. Eur J Hum Genet 22:969–978

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Philippakis AA, Azzariti DR, Beltran S, Brookes AJ, Brownstein CA, Brudno M et al (2015) The Matchmaker Exchange: a platform for rare disease gene discovery. Hum Mutat 36:915–921

    Article  PubMed  Google Scholar 

  • Reid JG, Carroll A, Veeraraghavan N, Dahdouli M, Sundquist A, English A et al (2014) Launching genomics into the cloud: deployment of Mercury, a next generation sequence analysis pipeline. BMC Bioinform 15:30

    Article  Google Scholar 

  • Ross LF, Rothstein MA, Clayton EW (2013) Mandatory extended searches in all genome sequencing: “incidental findings”, patient autonomy, and shared decision making. JAMA 310:367–368

    Article  CAS  PubMed  Google Scholar 

  • Rothberg JM, Leamon JH (2008) The development and impact of 454 sequencing. Nat Biotechnol 26:1117–1124

    Article  CAS  PubMed  Google Scholar 

  • Schaaf CP, Scott DA, Wiszniewska J, Beaudet AL (2011) Identification of incestuous parental relationships by SNP-based DNA microarrays. Lancet 377:555–556 (Erratum 377:812 (2011))

  • Scheuner MT, Peredo J, Benkendorf J, Bowdish B, Feldman G, Fleisher L et al (2015) Reporting genomic secondary findings: aCMG members weigh. Genet Med. 17:27–35

    Article  PubMed  Google Scholar 

  • Schuster SC, Miller W, Ratan A, Tomsho LP, Giardine B, Kasson LR et al (2010) Complete Khoisan and Bantu genomes from southern Africa. Nature 463:943–947

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sobreira N, Schiettecatte F, Valle D, Hamosh A (2015) GeneMatcher: a matching tool for connecting investigators with an interest in the same gene. Hum Mutat 36:928–930

    Article  PubMed  PubMed Central  Google Scholar 

  • Spence JE, Perciaccante RG, Greig GM, Willard HF, Ledbetter DH, Hejtmancik JF et al (1988) Uniparental disomy as a mechanism for human genetic disease. Am J Hum Genet 42:217–226

    CAS  PubMed  PubMed Central  Google Scholar 

  • Stankiewicz P, Lupski JR (2010) Structural variation in the human genome and its role in disease. Annu Rev Med 61:437–455

    Article  CAS  PubMed  Google Scholar 

  • Stephens PJ, Greenman CD, Fu B, Yang F, Bignell GR, Mudie LJ et al (2011) Massive genomic rearrangement acquired in a single catastrophic event during cancer development. Cell 144:27–40

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Warburton D (1988) Uniparental disomy: a rare consequence of the high rate of aneuploidy in human gametes. Am J Hum Genet 42:215–216

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wheeler DA, Srinivasan M, Egholm M, Shen Y, Chen L, McGuire A et al (2008) The complete genome of an individual by massively parallel DNA sequencing. Nature 452:872–876

    Article  CAS  PubMed  Google Scholar 

  • White J, Mazzeu JF, Hoischen A, Jhangiani SN, Gambin T, Alcino MC et al (2015) DVL1 frameshift mutations clustering in the penultimate exon cause autosomal-dominant Robinow syndrome. Am J Hum Genet 96:612–622

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • White JJ, Mazzeu JF, Hoischen A, Bayram Y, Withers M, Gezdirici A et al (2016) DVL3 alleles resulting in a− 1 frameshift of the last exon mediate autosomal-dominant Robinow syndrome. Am J Hum Genet 98:553–561

    Article  CAS  PubMed  Google Scholar 

  • Wiszniewska J, Bi W, Shaw C, Stankiewicz P, Kang SH, Pursley AN et al (2014) Combined array CGH plus SNP genome analyses in a single assay for optimized clinical testing. Eur J Hum Genet 22:79–87

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Wu N, Ming X, Xiao J, Wu Z, Chen X, Shinawi M et al (2015) TBX6 null variants and a common hypomorphic allele in congenital scoliosis. N Engl J Med 372:341–350

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang Y, Muzny DM, Reid JG, Bainbridge MN, Willis A, Ward PA et al (2013) Clinical whole-exome sequencing for the diagnosis of mendelian disorders. N Engl J Med 369:1502–1511

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Yang Y, Muzny DM, Xia F, Niu Z, Person R, Ding Y et al (2014) Molecular findings among patients referred for clinical whole-exome sequencing. JAMA 312:1870–1879

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zhang F, Lupski JR (2015) Non-coding genetic variants in human disease. Hum Mol Genet 24:R102–R110

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

Thanks to the Clinical Genomics pioneers, and to my colleagues in genetics and genomics at Baylor College of Medicine for their continued spirit of collaboration and collegiality. My gratitude is also extended to all members past and present in the Lupski Lab for their efforts and insights. The Lupski Laboratory is currently funded by the National Institute of Neurological Disease and Stroke (NINDS, R01NS058529), the National Institute of General Medical Sciences (NIGMS, R01GM106373), the National Human Genome Research Institute/National Heart Lung and Blood Institute Baylor Hopkins Center for Mendelian Genomics (NHGRI/NHLBI, U54HG006542), and the Smith Magenis Research Foundation; this work was also supported in part by NHGRI (U54HG003723) and the Intellectual and Developmental Disabilities Research Center, IDDRC (NICHD HD083092, Clinical Translational Core).

Author information

Authors and Affiliations

  1. Department of Molecular and Human Genetics, Baylor College of Medicine, 604B, One Baylor Plaza, Houston, TX, 77030, USA

    James R. Lupski

  2. Department of Pediatrics, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA

    James R. Lupski

  3. Human Genome Sequencing Center, Baylor College of Medicine, One Baylor Plaza, Houston, TX, 77030, USA

    James R. Lupski

  4. Texas Children’s Hospital, Houston, TX, 77030, USA

    James R. Lupski

Authors
  1. James R. Lupski
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to James R. Lupski.

Ethics declarations

Conflict of interest

J. R. L. is a paid consultant for Regeneron Pharmaceuticals, holds stock ownership in 23andMe and Lasergen, Inc., is on the scientific advisory board of Baylor Miraca Genetics Laboratories, and is a co-inventor on United States and European patents related to molecular diagnostics. The Department of Molecular and Human Genetics at Baylor College of Medicine derives revenue from molecular genetic testing offered at the Baylor Miraca Genetics Laboratories (BMGL; http://bmgl.com/).

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lupski, J.R. Clinical genomics: from a truly personal genome viewpoint. Hum Genet 135, 591–601 (2016). https://doi.org/10.1007/s00439-016-1682-6

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00439-016-1682-6

Keywords

Search

Navigation