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 the second part of the series (see here), we looked 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.
In the third and final part of the series, we’re 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 mitochondrial variants, structural aberrations and trinucleotide repeat expansions (including expansions of FMR1) with a single test.
Until recently, the cost of WGS has been prohibitive for use in routine testing. As prices for clinical grade WGS continue to drop significantly, the strengths of the technology are making it an increasingly attractive alternative to WES. To start with, WGS provides a comprehensive view of the genome. The coverage of exonic regions is actually superior to WES as WGS uses fragmentation methods of DNA preparation that avoid the DNA amplification challenges associated with WES. In addition to the exonic regions covered by WES, WGS covers all additional regions of the genome including introns, promoters and other regulatory regions that are increasingly being shown to be important in the understanding of human disease1. Because the sequencing data is complete and not dependent on an a priori list of genes, the data can simply be reanalyzed as new disease-variant and disease-gene associations are identified and described.
These reasons make it clear why WGS poses an attractive alternative to both WES and targeted gene analysis for identification of causative SNVs and indels. But WGS technology enables even greater benefits, making it possible to further shorten the diagnostic odyssey. Because of the consistent read depth observed in WGS data, it is possible to reliably detect larger structural variants. This includes copy number variants (CNVs) such as deletions and duplications as well as trinucleotide repeat expansions like the expanded CGG repeat sequence in the FMR1 gene that are typically investigated through fragile X syndrome testing.
The overall cost- and time-saving benefits offered by WGS are clear. And initial data on diagnostic yield are impressive. As published studies of clinical WGS begin to document the impact of a high diagnostic yield on downstream changes in clinical management, and to quantify the cost savings of using a single genetic test as the first-line of diagnosis, we can expect insurance companies to take notice and to begin providing reimbursement for clinical WGS.
1. Spielmann M and Mundlos S. Looking beyond the genes: the role of non-coding variants in human disease. Hum Mol Genet. 2016 Oct 1; 25 (R2): R157-R165. PubMed ID 27354350