Advances in Genetics: Incorporating, Molecular Genetic Medicine: 33

Personalized medicine: new genomics, old lessons
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Whole-exome sequencing WES identifies a known mutation in superoxide dismutase 1, soluble SOD1 , one of the known ALS genes for which the confidence level for its pathogenic potential is high, given that the allele has been seen in other patients and confirmed in the deceased brothers from the index case. However, the test also detected a heterozygous nonsense mutation in ciliary neurotrophic factor CNTF that was deemed insufficient to drive disease as neither deceased brother carried it, and it was found in three control exomes.

Such tools already exist for a small subset of disorders, most notably metabolic disorders, disorders of mitochondrial function and a handful of other conditions 98 , However, no clinical laboratories can or do carry out such tests, and the challenge remains for functional annotation to be incorporated into clinical-grade interpretation of results. We do not envisage a time when such non-human studies will become bona fide clinical tests, as not only will they remain expensive, labour-intensive, difficult to automate and challenging to interpret in the context of human mutation, but they are outside the scope of existing regulatory guidelines in the United States see the section below and BOX 2 on the regulation of genetic tests.

Our hope is that clinical testing laboratories may collaborate with functional modelling laboratories to inform the variant findings. Although there is no consensus on whether and how to share this information with a patient, there is broad agreement that results must be confirmed by a clinical laboratory before returning to a patient Some advocate returning only results with certain findings of high medical importance, whereas others have proposed tiered return of results on the basis of relative risk Some clinical laboratories are exploring informed consent models to allow patients to elect what information to disclose.

The Personal Genome Project, although not a clinical test, has taken the approach to return all secondary findings requested by the participant and to make WGS data on all participants publicly accessible , Ultimately, the duty to inform patients of predictable risks could be influenced by the legal pressure and threat of malpractice Paediatric genetic testing raises the additional ethical challenge of deciding whether to test or to disclose results for adult-onset genetic conditions.

A network of country-specific legislation protects Europeans from life and health insurance discrimination on the basis of genetics GINA prohibits genetic discrimination in most health insurance and employment scenarios. However, the provisions do not apply to life insurance, disability insurance or long-term care insurance Despite the HIPAA and GINA protections, the public remains nervous about genetic information being used against them , and physicians are wary of genetic information being included in medical records As the applications and utility both clinical and personal of genetic testing expand, so too does the risk that discovered genetic information could be used against individuals.

The protections of the existing US legal framework assuredly will be tested in courts. In the meantime, one key issue is how and where the delicate data resulting from WES and WGS clinical tests are hosted. The application of WES and WGS in the clinic has appropriately generated substantial debate in the community with regard to the delivery and impact of the information on physicians, patients and society in general — Much consideration has been given to the ethical implications of genomic information provided to research participants for example, see REFS — , but less is known about the implications in a clinical setting , BOX 2 discusses two of the key issues: Keeping pace with emerging clinical genetic technologies requires specialized genetic training as well as broad genetic literacy for patients and clinicians ordering and receiving genetics test results.

In reality, genetics literacy in the United States is sorely lacking from elementary school through to medical training , , By and large, the US public views genetics through the lens of genetic determinism. Implementation of genomic sciences into clinical applications requires that clinicians be sufficiently versed in genetics and genomics to prevent that the result of these tests are misunderstood or misused , The distinct role of the genetic counsellor in the genetics profession is extremely valuable in translating genetics and genomics concepts.

However, the dearth of professionals trained for this role necessitates centralized telemedicine to provide broad access to genetics services Recent efforts to push genetics curricula into medical and nursing schools to attract professionals led to the successful development of core genetics competencies in nursing and medicine , , Regulating genetic tests continues to challenge authorities attempting to protect patients and consumers from misguided misuse of genomic technologies.

This is not a new issue but one that continues to complicate existing models for regulating analytical and diagnostic tests in the United States BOX 3 and around the world.

For one, the analyte-specific model for regulating tests is no longer practicable when thousands or billions of analytes are assayed in a single clinical test. In addition, the burden on the regulator is evolving into one for regulating interpretation of rather than execution of results, authority for which is not clearly defined for genetic tests. CLIA certification is determined and maintained through CMS or through an independent accrediting body to verify quality standards and proficiency testing for example, the College of American Pathologists and The Joint Commission.

Genetic testing is not a speciality under CLIA so is usually regulated as a high-complexity chemistry test Several states provide additional state-specific oversight of LDTs, and New York State requires evaluation of clinical validity for state certification. Recent focus on regulation of genetic tests stem in part from the advent of direct-to-consumer marketing and offering of personal genetic and genomic tests In addition to regulatory authority, guidelines for testing may be developed by professional organizations, such as the American College of Medical Genetics, for both rare disease diagnostics and broader technological platforms designed for risk prediction.

The analytical validity of most genetic tests is fairly high in comparison to other chemical assays subject to CLIA certification. However, the clinical validity can vastly vary depending on the genotype and the corresponding phenotype. As such, the crux of regulation of genetic tests lies not with the evaluation of the analytical validity of the IVD device or laboratory-developed test LDT but with the interpretation of any discovered genomic variants in context of a particular patient and a particular phenotype. Moreover, newer NGS technologies for example, microarrays and whole-exome and whole-genome sequencing interrogate tens of thousands of analytes rather than a single or a few analytes.

It is unclear at this point how to develop sufficient evidence for test validation, what controls are appropriate for such tests and how to establish proficiency routinely within a laboratory. Until recently, physician and patient information exchange has been asymmetrical, if not paternalistic: However, it is clear that people with Internet access will seek medical information online , , refuting the idea that patients want only a small amount of information or nothing more than a prescriptive regimen.

We expect crowd-sourcing to raise funds for rare disease testing or to create online communities to be integral to genetic interpretation on a personal level. Current evidence indicates that most people want to know their genetic test results and want choice in whether and how to access this information , — With increasing public interest in and attention to genetic services and decreasing availability of genetic experts to filter the information, patients are likely to seek their own modes of information gathering.

As genome sequencing enters the clinical realm, we must develop ways to communicate relevant findings to best inform clinical practice while remaining alert to the dangers of genetic determinism. Genetic variants that appear to precipitate a phenotype may also depend on environmental factors, modifier genes, epigenomics and the additive and synergistic effects from multiple variants Even simple genetic test results can be misunderstood in clinical translation Thus, communicating complex genomic results with a range of interpretations is challenging to say the least. The availability of clinical genetic diagnostics in the United States depends on the practicability of both development of laboratory tests and payment for laboratory services.

Clinical diagnostic laboratory directors select tests for development that will fit into existing throughput platforms, maximize efficiency and costs, and be subject to minimal competition. Laboratories that hold gene patents or that have exclusive licences for genetic testing benefit from such intellectual property by restricting test development and offerings by competing laboratories , Newer technologies carry the additional costs of validation of novel platforms for clinical use, whereas WES and WGS in particular carry substantial costs in long-term data storage and informatics for interpretation of genomic variation.

Reimbursement of genetic testing services by payers depends on the level of evidence for clinical utility or it should do , the impact of such services on clinical decision making and the cost-effectiveness of genetic testing for a diagnosis — With these economic constraints, diagnostic tests for rare diseases are not as commercially profitable as the tests for common disorders, given the expense of validation and proficiency testing. Integration of clinical diagnostics into practice depends on the speciality that is being considered for testing, but clinical decision support tools are vital for introducing testing options into hospital and outpatient workflow, particularly within EMRs , The continued erosion of sequencing costs, driven in part by increased capacity of existing technologies and improvements in chemistry, as well as the emergence of single-molecule third- and fourth-generation sequencing , , such as nanopore sequencing 64 , suggest that in the fullness of time, most patients entering the health-care system will have had their genome sequenced before clinical evaluation.

Therefore, the composition of genetic testing will be fundamentally altered to focus on interpretation of genomic data in the context of an individual, their immediate and long-term needs, their personal choices and their environment. This will not be an overnight revolution, not least because it will be some time before emergent genomic technologies are of a sufficient quality and of a low enough cost to be accessible to most of the world population that does not have access to high-quality health care.

It is almost certain that technological problems relating to accuracy of sequencing information will shortly be solved; however, the same is not true for the challenges in interpretation. Although a detailed discussion of interpretation paradigms deserves detailed scholarly study and robust discussion among basic sciences, clinicians and policy makers, it is important to highlight some key points.

The scientific community has heavily focused on the sequencing of phenotypic extremes, derived models of genetic architecture and allelic causality from these extremes, and is now seeking to superimpose these models on the general population. Given that we have at present a poor understanding of the effect of individual alleles that are superimposed on the genetic context of the rest of the genome, these assumptions are premature. We now understand that each individual can carry dozens of nonsense mutations, some of which appear to lie in genes thought to be crucial to biological function However, discarding such alleles from clinical relevance could be fundamentally flawed in the context of other alleles, epialleles and environmental exposures.

Likewise, we are troubled by the flaws in the approaches to sequencing for prenatal defects from maternal fetal blood as a guiding tool, as such efforts are still grounded on a narrow view of genetic causality. It is important to stress that, given our limited ability to predict phenotypic outcomes on the basis of the genotype, offering pre-emptive guidance might be catastrophic.

From our own work, we understand that patients bearing the MR allele in BBS1 may have no phenotype, may develop isolated retinal degeneration or may experience the full spectrum of Bardet—Biedl syndrome. Finally, variable penetrance and variable expressivity remain acute problems in clinical management and interpretation, the genetic basis of which must be understood more fully to improve the clinical utility of WGS data , We strongly encourage the systematic study of both patient and control populations wherein genomic data are systematically annotated with detailed clinical information and physiologically relevant biological assays.

We propose that these activities will be necessary to gain a sufficient understanding of the genetic architecture of human pathology and to improve the validity of computational prediction algorithms to the point at which their implementation in the clinical setting can be executed with confidence. Finally, amid the discussion of what information should be delivered and how, we must be diligent to avoid genetic exceptionalism and threatening paternalistic approaches.

Rather, we should work on bilateral communication mechanisms and policies that facilitate the exchange of annotated genetic information, accompanied by lucid assessment of the shortcomings and risks of such data, between clinical laboratories and patients. The authors thank E. Angrist for their thoughtful suggestions for this manuscript. National Center for Biotechnology Information , U. Author manuscript; available in PMC Jun 9.

Sara Huston Katsanis 1 and Nicholas Katsanis 2. The publisher's final edited version of this article is available at Nat Rev Genet. See other articles in PMC that cite the published article. Abstract Genomic technologies are reaching the point of being able to detect genetic variation in patients at high accuracy and reduced cost, offering the promise of fundamentally altering medicine.

The scope of clinical genetic testing Genetic testing has grown from a niche speciality for rare disorders to a broad scope of applications for complex disease and personal use 17 , Table 1 Factors considered in selecting a genetic test. Open in a separate window.

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Table 2 Clinical genetic testing methodologies. Costs of the testing will widely vary from one laboratory to the next; however, these estimates are based on the charge of the test from a sampling of laboratories, not on the costs of consumables or the reimbursed amount.

However, only the indicated approaches will detect uniparental disomy in absence of the parental genetic samples. Table 3 Evaluating the validity of genetic tests. Indirect testing Despite the surge of new technologies to interrogate disease-causing variants in a patient in well-funded laboratories, indirect methodologies continue to have a prominent role in diagnostics in regions of the world with more limited resources and thus a substantial fraction of the human population ; in particular, linkage analysis using single-nucleotide polymorphisms SNPs and short tandem repeats STRs can be applied Targeted allele-specific mutation detection Amplification combined with restriction digest, hybridization or another means of detecting a mutation remains among the cheapest and most robust methods in clinical molecular diagnostics.

Genome-wide SNP microarrays Microarray-based genotyping can be divided into three main applications: Detection of structural and chromosomal variation Recent improvements in chemistry and microscopy have substantially augmented the resolution of cytogenetics, most notably through the development of multi-probe fluorescent in situ hybridization FISH; for a detailed review, see REF. Whole-genome and whole-exome sequencing NGS uses powerful massively parallel sequencing assays to sequence many genes of interest, the whole exome or the whole genome for variants in a broad range of rare and complex disorders.

Evolving results The success cases in rare diseases of WES are promising 72 — 74 ; however, routine clinical genomic sequencing is waft with complications, resulting from both its unprecedented scale and interpretive challenges.

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A probabilistic disease-gene finder for personal genomes. Crit Rev Oncol Hematol. Box 1 Variant interpretation: A challenge in the transition from genetics to genomics is the complexity of information; genomic variants may play etiologic roles for a spectrum of diseases, and interact with other variants and environmental factors Conti et al. Lyon GJ, et al. This paper describes the challenges of handling genome-wide data in a research setting.

Causal disease variants In clinical diagnostic genetic testing, the American College of Medical Geneticists 81 recommends that variants be assigned to one of the following six categories: Box 1 Variant interpretation: Box 2 Ethical considerations for genetic testing. Privacy and discrimination A network of country-specific legislation protects Europeans from life and health insurance discrimination on the basis of genetics Other considerations Ethical considerations The application of WES and WGS in the clinic has appropriately generated substantial debate in the community with regard to the delivery and impact of the information on physicians, patients and society in general — Genetic education Keeping pace with emerging clinical genetic technologies requires specialized genetic training as well as broad genetic literacy for patients and clinicians ordering and receiving genetics test results.

Regulatory policy and standards Regulating genetic tests continues to challenge authorities attempting to protect patients and consumers from misguided misuse of genomic technologies. Box 3 US regulatory policy and standards for genetic testing: Mode of delivery Until recently, physician and patient information exchange has been asymmetrical, if not paternalistic: Costs, coverage and implementation The availability of clinical genetic diagnostics in the United States depends on the practicability of both development of laboratory tests and payment for laboratory services.

Conclusions The continued erosion of sequencing costs, driven in part by increased capacity of existing technologies and improvements in chemistry, as well as the emergence of single-molecule third- and fourth-generation sequencing , , such as nanopore sequencing 64 , suggest that in the fullness of time, most patients entering the health-care system will have had their genome sequenced before clinical evaluation.

Acknowledgments The authors thank E. Glossary Large-insert clone A large haplotype fragment that is inserted into, for example, a bacterial artificial chromosome Oligonucleotide arrays Hybridization of a nucleic acid sample to a very large set of oligonucleotide probes, which are attached to a solid support, to determine sequence, to detect variations or to carry out gene expression or mapping Exome The collection of protein-coding regions exons in the genome.

Usually, there are two copies of each locus, but if, for example, duplications or triplications occur, then the number of copies will increase Variants of unknown significance VUSs Alterations in the sequence of a gene, the significance of which are unclear Genetic determinism The idea that genes and genetic variants are the primary factor determining and shaping human traits Epigenomics Describes a heritable effect on chromosome or gene function that is not accompanied by a change in DNA sequence but rather by modifications of chromatin or DNA Epialleles An epigenetic variant of an allele.

The activity of an epiallele is dependent on epigenetic modifications such as histone deacetylation or cytosine methylation Genetic exceptionalism The view that genetic information, traits and properties are qualitatively different and deserving of exceptional consideration. Footnotes Competing interests statement The authors declare no competing financial interests. Pasche B, Absher D. Charting a course for genomic medicine from base pairs to bedside. Bainbridge MN, et al.

Whole-genome sequencing for optimized patient management. Berg JS, et al. Next generation massively parallel sequencing of targeted exomes to identify genetic mutations in primary ciliary dyskinesia: Choi M, et al. Genetic diagnosis by whole exome capture and massively parallel DNA sequencing.

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Lupski JR, et al. Whole-genome sequencing in a patient with Charcot—Marie—Tooth neuropathy. N Engl J Med. Exome sequencing deciphers rare diseases. Ng SB, et al. Exome sequencing identifies the cause of a Mendelian disorder. Identification by whole-genome resequencing of gene defect responsible for severe hypercholesterolemia. Roach JC, et al. Analysis of genetic inheritance in a family quartet by whole-genome sequencing. Worthey EA, et al.

Medical genetics - Wikipedia

Making a definitive diagnosis: Genomic sequencing in clinical trials. Quail MA, et al. A tale of three next generation sequencing platforms: Liu L, et al. Comparison of next-generation sequencing systems. Advances in prenatal screening: This Review covers prenatal screening strategies from ultrasound scans to genome-wide molecular tests and considers the important ethical questions concerning reproductive choice, autonomy rights of future children, equity of access and the proportionality of testing. Sequeiros J, et al. The wide variation of definitions of genetic testing in international recommendations, guidelines and reports.

Kiezun A, et al. Exome sequencing and the genetic basis of complex traits. Kitzman JO, et al. Noninvasive whole-genome sequencing of a human fetus. Lipman PJ, et al. On the analysis of sequence data: Massaro JD, et al. Analysis of five polymorphic DNA markers for indirect genetic diagnosis of haemophilia A in the Brazilian population. Michaelides M, et al. Mutations, clinical findings and survival estimates in South American patients with X-linked adrenoleukodystrophy.

Phylipsen M, et al. Kearns WG, et al. Preimplantation genetic diagnosis and screening.

Medical genetics

This paper reviews the scope of PGD to identify genetic abnormalities prior to embryo transfer and the techniques used for single cell detection of genetic variants. Laurie AD, et al. Preimplantation genetic diagnosis for hemophilia A using indirect linkage analysis and direct genotyping approaches. Detection of unstable trinucleotide repeats. Is the DNA sequence the gold standard in genetic testing?

Quality of molecular genetic tests assessed. Sequencing of genomic DNA by combined amplification and cycle sequencing reaction. A general approach for improving cycle-sequencing that facilitates a robust one-step combined amplification and sequencing method. FGFR -related craniosynostosis syndromes. Noonan syndrome and clinically related disorders.

Hageman GS, et al. Clinical validation of a genetic model to estimate the risk of developing choroidal neovascular age-related macular degeneration. A genetic approach to stratification of risk for age-related macular degeneration. Copy number and SNP arrays in clinical diagnostics. Annu Rev Genom Hum Genet. Meschia JF, et al. Genomic risk profiling of ischemic stroke: Tiu RV, et al. Prognostic impact of SNP array karyotyping in myelodysplastic syndromes and related myeloid malignancies. Concordance study of 3 direct-to-consumer genetic-testing services.

Reid RJ, et al. Association between health-service use and multiplex genetic testing. Haines JL, et al. Complement factor H variant increases the risk of age-related macular degeneration. Klein RJ, et al. Complement factor H polymorphism in age-related macular degeneration. Edwards AO, et al. Complement factor H polymorphism and age-related macular degeneration. Gold B, et al. Variation in factor B BF and complement component 2 C2 genes is associated with age-related macular degeneration.

Despriet DD, et al. Complement factor H polymorphism, complement activators, and risk of age-related macular degeneration. Fluorescence in situ hybridization. Applications of array comparative genomic hybridization in obstetrics. Obstet Gynecol Clin North Am. Swaminathan GJ, et al. Web-based, community resource for clinical interpretation of rare variants in developmental disorders. Wapner RJ, et al. Chromosomal microarray versus karyotyping for prenatal diagnosis.

This paper compares the accuracy, efficacy and yield of chromosomal microarray analysis to karyotyping as a primary diagnostic tool for the evaluation of developmental delay and structural malformations in children. New applications and developments in the use of multiplex ligation-dependent probe amplification. This paper describes the MLPA technique and explores its utility in copy number variation diagnostics.

The scope of clinical genetic testing

Hills A, et al. Talkowski ME, et al. Sequencing chromosomal abnormalities reveals neurodevelopmental loci that confer risk across diagnostic boundaries. Deploying whole genome sequencing in clinical practice and public health: Cooper GM, Shendure J. Needles in stacks of needles: A Review of approaches is presented here for determining pathogenicity of single-nucleotide variants using comparative and in silico functional genomics. What can exome sequencing do for you?

Need AC, et al. Clinical application of exome sequencing in undiagnosed genetic conditions. Mayer AN, et al. A timely arrival for genomic medicine. The advent of personal genome sequencing. Human genome sequencing in health and disease. Branton D, et al. The potential and challenges of nanopore sequencing. Genome-wide detection of chromosomal rearrangements, indels, and mutations in circular chromosomes by short read sequencing.

Identifying insertion mutations by whole-genome sequencing. Sequencing technologies — the next generation. Hedges DJ, et al. Comparison of three targeted enrichment strategies on the SOLiD sequencing platform. Quail M, et al. Sulonen AM, et al. Comparison of solution-based exome capture methods for next generation sequencing. Ashley EA, et al. Clinical assessment incorporating a personal genome. Saunders CJ, et al. Rapid whole-genome sequencing for genetic disease diagnosis in neonatal intensive care units.

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Rauch A, et al. Range of genetic mutations associated with severe non-syndromic sporadic intellectual disability: Diagnostic exome sequencing in persons with severe intellectual disability. Roberts NJ, et al. The predictive capacity of personal genome sequencing. Chen R, et al. Personal omics profiling reveals dynamic molecular and medical phenotypes. Zuvich RL, et al. Pitfalls of merging GWAS data: Pathak J, et al. Evaluating phenotypic data elements for genetics and epidemiological research: McCarty CA, et al. The futility of genomic counseling: Richards CS, et al.

ACMG recommendations for standards for interpretation and reporting of sequence variations: ACMG developed recommendations for standards for interpretation of sequence variations.

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Stenson PD, et al. The Human Gene Mutation Database: Bale S, et al. Loss-of-function variants in the genomes of healthy humans. MacArthur DG, et al. A systematic survey of loss-of-function variants in human protein-coding genes. This paper determined how many genetic variants predicted to cause loss of function of protein-coding genes humans carry.

Massively parallel sequencing and rare disease. Adzhubei IA, et al. A method and server for predicting damaging missense mutations.

What is DNA and How Does it Work?

Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm. Stone EA, Sidow A. Physicochemical constraint violation by missense substitutions mediates impairment of protein function and disease severity. Robinson PN, et al. The Human Phenotype Ontology: Am J Hum Genet. Sprague J, et al. The Zebrafish Information Network: Evaluation of genomic high-throughput sequencing data generated on Illumina HiSeq and genome analyzer systems. Houdayer C, et al. Evaluation of in silico splice tools for decision-making in molecular diagnosis.

A web resource to identify exonic splicing enhancers. Yandell M, et al. A probabilistic disease-gene finder for personal genomes. Pelak K, et al. The characterization of twenty sequenced human genomes. Zaghloul NA, et al. Functional analyses of variants reveal a significant role for dominant negative and common alleles in oligogenic Bardet—Biedl syndrome. Chassaing N, et al. OTX2 mutations contribute to the otocephaly—dysgnathia complex.