As a three-part series, we’re exploring how the standard of care, as it pertains to genetic testing, is evolving for rare disease diagnosis. In the first part of the series (take a look here), we reviewed the traditional approach to genetic testing by following the typical diagnostic journey of a young child with symptoms of developmental delay. We covered fragile X syndrome testing via PCR and Southern blot analysis, array CGH analysis for large structural aberrations and targeted gene analysis for single nucleotide variant (SNV) changes and small (<20bp) indels.
In this second part we’re looking at how whole exome sequence (WES) testing is increasingly being accepted as an alternative to targeted gene analysis, for faster and more cost-effective identification of causative SNVs and indels.
Continuing with our example diagnostic journey, following negative fragile X syndrome and array CGH tests, a typical next step would be to order targeted sequencing of FMR1. Which may potentially be followed by targeted sequencing of additional genes like MECP2, CDKL5, and others that have also been associated with developmental delay. Or to order simultaneous testing of increasingly larger set of developmental delay associated genes as part of next generation sequencing (NGS) panels. The advantage of the latter approach being that more genes can be screened at once, significantly reducing the time between individual tests.
During the assay development process, the content, or gene list, comprising an NGS panel is typically selected based on variant-disease and gene-disease associations described in the published literature or variant databases. But once the gene list has been selected, it is difficult to make changes to the assay as new information becomes available regarding additional variants and genes associated with the disorder. The introduction of clinical WES has helped address this problem. Designed to simultaneously provide information about the ~20,000 genes that make up the human genome, exome testing offers great promise for providing a more comprehensive view of potential causative mutations while reducing the time between individual gene or panel tests.
In recent years, a number of studies of clinical WES have been published in an effort to investigate its clinical utility and cost effectiveness compared to more traditional genetic testing. Initial studies considered individual cases. In the last few years, a number of retrospective studies have been performed which analyzed the outcome of exome testing. More recently, prospective studies have evaluated WES as a first-tier test in comparison to standard methods of single and multi-gene panel sequencing1,2,3. These studies have shown that WES’s rate of diagnosis, clinical utility, and resulting impact on clinical management argues strongly for WES as a first-line genetic test in a wide variety of situations including cases of monogenic disorders as well as neurodevelopmental disorders such as intellectual disability and global developmental delay.
Based in part on the conclusions drawn from these studies, more and more insurance companies are amending their genetic testing policies to provide reimbursement for exome testing. Reimbursement is often supported in cases where the patient has been counseled about the risks, genetic etiology is believed to be the most likely explanation for the phenotype and there is potential for a change in management and clinical outcome. As of the writing of this post, Cigna, Geisinger Health Plan, United Healthcare and Blue Cross Blue Shield companies in multiple states, including Massachusetts and California, all support reimbursement for exome testing under certain conditions.
In the third and final part of the series we’ll be looking at how the standard of care is continuing to evolve, as clinical whole genome sequence (WGS) testing enables a more comprehensive view of the exome while simultaneously identifying structural aberrations and trinucleotide repeat expansions (including expansions of FMR1) with a single test.
1. Start Z, et al. A prospective evaluation of whole-exome sequencing as a first-tier molecular test in infants with suspected monogenic disorders. Genet Med. 2016 Nov;18(11):1090-1096. PubMed ID 26938784
2. Tan TY, et al. Diagnostic impact and cost-effectiveness of whole-exome sequencing for ambulant children with suspected monogenic conditions. JAMA Pediatr. 2017 Sep 1;171(9):855-862. PubMed ID 28759686
3. Vissers LELM, et al. A clinical utility study of exome sequencing versus conventional genetic testing in pediatric neurology. Genet Med. 2017 Sep;19(9):1055-1063. PubMed ID 28333917