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Molecular Genetic Testing and the Future of Clinical Genomics

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Molecular Genetic Testing and the Future of Clinical Genomics REVIEWS TRANSLATIONAL GENETICS Molecular genetic testing and the future of clinical genomics Sara Huston Katsanis1 and Nicholas Katsanis2 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. Still, although scientists and policy advisers grapple with how to interpret and how to handle the onslaught and ambiguity of genome-wide data, established and well-validated molecular technologies continue to have an important role, especially in regions of the world that have more limited access to next-generation sequencing capabilities. Here we review the range of methods currently available in a clinical setting as well as emerging approaches in clinical molecular diagnostics. In parallel, we outline implementation challenges that will be necessary to address to ensure the future of genetic medicine. Large-insert clone Molecular diagnostic testing in a symptomatic individual Here we review a range of methods available for A large haplotype fragment has become increasingly sophisticated. Until recently, molecular diagnosis, their relative value for detecting that is inserted into, for such testing was carried out on, at most, one or a few genomic variation and some key challenges for each example, a bacterial artificial loci. The advent of large-insert clone arrays and, later, technology. With the rapidly changing technological chromosome. oligonucleotide arrays changed this landscape by allow- platforms, we direct the reader to other articles for Oligonucleotide arrays ing a patient’s entire genome to be queried at improved comparisons of next-generation sequencing (NGS) and Hybridization of a nucleic acid resolution, thereby allowing the detection of medium to other genomic technology reviews12–14. Further, we dis- sample to a very large set of large genomic lesions. Today, this can be done at single- cuss the challenges of implementing these technologies oligonucleotide probes, which nucleotide resolution thanks to cheaper, faster and into clinical practice, including policy development are attached to a solid support, exome to determine sequence, to increasingly accurate whole- sequencing (WES) and ethical considerations. Although we concentrate 1 detect variations or to carry and whole-genome sequencing (WGS) . Although our Review on laboratory testing in the United States, out gene expression or genome sequencing is expected to transform diagnos- as it is a focal point for policy discussion and tech- mapping. tics, non-sequencing molecular technologies remain nological development, we present approaches to be crucial for efficiently and precisely screening and defin- considered in other countries and regions with more ing variation. Patients and families rely on molecular limited resources. We also focus on genetic testing for diagnoses for health-care management, disease prog- heritable genotypes or karyotypes as opposed to somatic nosis and family planning, and they personally benefit mutations in cancer or viral load genetic testing. We when an answer is provided for the afflicting condition. do not cover newborn screening technologies, ancestry Amid the euphoria surrounding these advances, testing or identity DNA testing; for a scholarly discus- major analytical and interpretative challenges have sion of prenatal genetic testing and ethical considera- 1Duke Institute for Genome emerged, ranging from the validation of large numbers tions, see REFS 15,16. We start with a discussion of the Sciences and Policy, Duke of genomic changes in a patient, to the economic feasi- scope of genetic services and applications and current University Medical Center, bility of this approach and its deployment in standard relevant technologies. We then focus on the challeng- Durham, North Carolina 27710, USA. care, to managing the terabytes of data that accompany ing interpretation of genome variation, particularly 2 2Center for Human Disease a single sequenced genome . Deciphering the informa- in the nascent use of WGS and WES. Finally, we discuss Modeling, Duke University tion that is locked in a patient’s genome is not trivial. the breadth of considerations and social implications Medical Center, Durham However, the effort invested towards development of of clinical genome sequencing, including access, eth- North Carolina 27710, USA. informatic and molecular tools that are immediately ics, genetics education and the regulatory landscape. At e-mails: sara.katsanis@duke. edu; nicholas.katsanis@duke. applicable to both common and rare genetic disease the conclusion of this Review, we discuss the upcom- edu has the potential to inform a broad range of clinical ing challenges to integrating the next wave of genome doi:10.1038/nrg3493 phenotypes3–11. sequencing into clinical practice. NATURE REVIEWS | GENETICS VOLUME 14 | JUNE 2013 | 415 © 2013 Macmillan Publishers Limited. All rights reserved REVIEWS Exome The scope of clinical genetic testing to be impractical for routine screening. Genetic tests in The collection of Genetic testing has grown from a niche speciality for rare under-funded regions may continue to be driven by the protein-coding regions (exons) disorders to a broad scope of applications for complex candidate gene approach on the basis of the phenotype in the genome. As exons disease and personal use17,18. Not surprisingly, the defi- of a patient, as has been the paradigm in the United comprise only 1% of the genome and contain the nition of a genetic test has changed as the applications States for two decades. Still, these approaches hold a most easily understood have evolved. Applications of clinical genetic testing valuable role in certain classic monogenic syndromes and functionally relevant span medical disciplines, including: newborn screening and in families with a previously attributed molecular information, sequencing of for highly penetrant disorders; diagnostic and carrier cause. However, in naive cases for genetic work‑up, an only the exome is an efficient testing for inherited disorders; predictive and pre- argument could be made that (not accounting for cost) method of identifying many variants that are likely to affect symptomatic testing for adult-onset and complex disor- whole-genome analysis may be valuable in determin- a trait. ders; and pharmacogenetic testing to guide individual ing mutation load and identifying other genetic factors drug dosage, selection and response (TABLE 1). Currently, relevant to health planning. Next-generation sequencing genetic tests may be indicated in different clinical con- (NGS). NGS platforms Post-millennium genetic technologies sequence as many as billions texts and ordered by multiple health-care providers (see of DNA strands in parallel, Further information for resources of available genetic For the most part, clinical molecular diagnostic tech- yielding substantially more tests). The circumstances of the individual genetic test nologies remain focused on identifying patients’ throughput than Sanger — including the acute nature of the phenotype, the age underlying pathogenic mechanisms. TABLE 2 summa- sequencing and minimizing the of the patient, family history and specimen availability rizes the methodologies that are applicable to heritable need for the fragment-cloning methods that are often used in — guide the selection of tests and test platforms. For genotypes and karyotypes. With direct genetic testing, Sanger sequencing of example, prenatal WGS can detect carrier status for a the laboratory looks for the particular genetic variant genomes. host of rare genetic disorders19 but might be considered (or variants) that contributes to a condition, whereas Table 1 | Factors considered in selecting a genetic test Test Description Example Embryo or Fetus (prenatal Child Adult blastocyst (pre- testing) implantation genetic diagnosis) Newborn Targeted tests for recessive Phenylketonuria, Not applicable Not applicable Tests provided Not screening genetic disorders cystic fibrosis, at birth vary by applicable sickle-cell country and state anaemia or region Diagnostic Confirmatory test or Skeletal Specimen type and limited available amount Where treatment is desired, testing differential diagnosis dysplasias, for sampling may restrict platform selection turnaround time may restrict testing for a symptomatic thalassaemias, (for example, WES or WGS versus SNP or platform selection individual craniosynostoses STR typing) Turnaround time necessary may restrict platform selection Carrier testing Targeted testing for Cystic fibrosis, Applied typically for rare disease but Carrier testing According asymptomatic individuals thalassaemias, applicable for other familial mutations of minors is to standard potentially carrying one or Tay–Sachs considered in of care more recessive mutation disease the context of individual paediatric cases164,165 Predictive Tests for variants causing Most cancers, Some have discouraged genetic testing of asymptomatic minors According testing or associated with cardiovascular for adult-onset conditions to standard diseases or disorders with disease, diabetes of care a hereditary component, usually with adult-onset symptoms Pre-symptomatic Tests for variants causing Huntington’s Some have discouraged genetic testing of asymptomatic minors According testing or associated with diseases disease, haemo- for adult-onset conditions152,153 to standard or disorders known to be chromatosis, of care inherited in the family,
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