Molecular genetic testing is a key tool in the evaluation of patients with metabolic and endocrine diseases. The three most serious issues that must be considered prior to undertaking diagnostic molecular testing are: 1) selection of the most appropriate test; 2) correct interpretation of test results; and 3) cost, stewardship, and appropriate utilization of medical resources. Selection of the most appropriate test is key because doing this mitigates the other two concerns. The physician selecting the test must understand the sensitivity and specificity of the selected test in the context of the patient’s findings. Molecular test results are complex and require significant expertise to interpret. A provider should not order a test if he or she is not prepared to deal with all possible results including indeterminate or novel results. Furthermore, although the cost of molecular testing is rapidly decreasing, it remains expensive, and ordering the wrong test or being unable to interpret test results will lead to waste of healthcare resources.
Unfortunately, on top of the issues listed above, the rapid increase in demand and availability of genetic tests has overtaken the availability of experienced providers as well as any realistic efforts to systematically evaluate the clinical utility and value of genetic testing. New genetic tests are becoming much more rapidly available than the respective assessments of their clinical utility and value for patient management can be ascertained, let alone any determinations of their most rational or most ethical use.
The magnitude of the increase in clinical genetic testing can be seen in the GeneTests database (http://www.ncbi.nlm.nih.gov/sites/GeneTests/?db=GeneTests). GeneTests is a voluntary registry of laboratories that offer commercial human genetic testing for clinical purposes. Almost all US–based commercial laboratories and a fairly large subset of international ones have listed their test menus in this database. Since its inception in 1990 there has been a steady increase in the number of laboratories offering clinical genetic testing from about 100 registered laboratories in 1990 to about 500 by the year 2000. This was accompanied by an increase in the number of genetic diseases for which testing was available, from about 100 to around 800. However, while the 21st century saw only a minor further increase in the number of registered testing facilities (~650 total in 2015), the genetic test menu grew exponentially to ~44,000 tests by mid 2015.
The last 5 to 10 years have also seen an explosion in the use of novel, high throughput, high resolution techniques, such as genomic microarrays (array-comparative genomic hybridization [array-CGH], and single nucleotide polymorphism arrays [SNP-arrays]) that have revolutionized genome-wide copy number determination and Next Generation (NexGen) DNA sequencing, which is poised to replace conventional Sanger sequencing.1,2,3,4,5,6,7,8 Since NexGen sequencing offers vastly increased sequence coverage at a fraction of the cost of Sanger sequencing, the pace of implementation of new genetic ...