Journal Article

Molecular genetic testing and the future of clinical genomics

Katsanis, Nicholas, Katsanis, Sara Huston

2013

Overview

Key Points Clinical molecular genetic testing is transforming personalized medicine and is appropriate for a range of applications, such as rare disease diagnostics and predictive testing for common disorders. Whole-exome and whole-genome sequencing may become a first-line clinical test for some naive diagnostic cases, but classic genetic tests will continue to be used for the high analytical sensitivity of specific defects and for the confirmation of genome findings. There remains no single test to detect the wide array of genetic defects that may be inherited or arise de novo ; clinical diagnostics requires multiple approaches to determine a causal genetic defect. Although genome sequencing may transform diagnostic approaches in large academic medical centres, access to expensive and sophisticated tests are not universal. Genetic testing must be available globally through validated simple technologies for molecular diagnostics (such as direct PCR, linkage analysis or multiplex ligation-dependent probe amplification). The greatest challenge to clinical genomics is the reliable interpretation of the multiple and novel variants found through genome sequencing. Pathogenicity of genetic variants can be examined with bioinformatics prediction approaches, protein stability studies, transcriptional activity studies and allele- and/or gene-specific animal models. As broader genomic information becomes available to providers and patients, partnerships will develop to convey patient-centred data, including incidental findings. The regulatory environment must adapt to the coming volume of genomic information to maximize benefit to patients and health-care systems and to match the expectations of the patient population with regard to these technologies. The authors review current technologies for clinical genetic testing. Moves are being made towards whole-genome and whole-exome sequencing in the clinic, although other technologies will continue to be of value. 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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: Agriculture / Animal Genetics and Genomics / Animals / Biomedical and Life Sciences / Biomedicine / Cancer Research / Evaluation Studies as Topic / Forecasts and trends / Gene Function / Genetic screening / Genetic Testing - economics / Genetic Testing - ethics / Genetic Testing - legislation & jurisprudence / Genetic Testing - standards / Genome-Wide Association Study / Genomics / Human Genetics / Humans / Karyotyping / Medical genetics / Methods / Molecular diagnostic techniques / Molecular Diagnostic Techniques - economics / Molecular Diagnostic Techniques - ethics / Molecular Diagnostic Techniques - standards / Molecular genetics / Oligonucleotide Array Sequence Analysis / Polymorphism, Single Nucleotide / review-article / Sequence Analysis, DNA / United States