The advent of next generation sequencing has made it possible to now understand and identify genetic variations associated with rare genetic diseases. One of the popular approaches which has found widespread applications has been exome sequencing, which involves sequencing of the exons of protein-coding genes using a targeted capture method. This article provides a general overview of exome sequencing, its applications and caveats. The article also provides an introduction to the Genomics for Understanding Rare Diseases-India Alliance Network (GUaRDIAN) and how the network could be helpful to address specific clinical queries with regard to rare genetic diseases in your practice.
The last decade saw the sequencing of the complete human genome . This was followed by remarkable advances in technologies that enabled quick, efficient and affordable sequencing of personal genomes. These technologies have been popularly called next generation sequencing technologies (NGS), differentiating them from the earlier and conventional technologies, which were slow and cumbersome and largely more expensive . These advances and the availability of genomic information of a large number of individuals provides a template for a significant change in the way we practice medicine in the future . It is widely believed that genomic information would increasingly be used to prevent, predict and offer precise management strategies for several human diseases .
The availability of advanced technology in the recent years to sequence whole or part of the genome of individuals have significantly added to our understanding of genetic diseases, especially rare genetic diseases. Rare genetic diseases are by definition, diseases caused by mutations in the genome and occur at a prevalence of less than one in 100,000 individuals. Although individually they occur less frequently, rare genetic disease encompass a spectrum of approximately over 7,000 unique diseases, that add a significant cumulative disease burden . It is estimated that in the United States, rare genetic diseases in total affect one in every 10 individuals. Of the 7,000 odd diseases, the genetic mutation has been characterized for only approximately a half of the disorders. One of the major impact and application of genomic technologies have been the understanding of genetic variations in the genomes of individuals and how these variations could be associated with diseases and traits [6,7]. A variety of genomic technologies which offer genomic assays at different resolutions are available today, and have been extensively been utilised by researchers to understand the correlations or associations with human diseases and traits. The advent of next generation sequencing has in the recent years seen widespread application of the technology in hunting for genetic mutations in diseases, significantly adding to the known genetic associations with diseases in the very recent years.
Though largely these technologies have been exploited in the research domain, to discover genetic mutations and associations with diseases, the widespread use and distinct utility has in the recent years spilled over to clinical medicine. The blurring boundaries between the research and clinical applications have seen clinicians increasingly utilising the power of NGS to arrive at fast and precise diagnosis of conditions in clinical settings . This article introduces one such application- exonerated sequencing in clinical diagnosis of rare genetic diseases.
As you would have imagined, sequencing of this compendium of exons would potentially encompass a majority of the functional regions of the genome important to code for proteins, and sequencing this region would potentially enable us to quickly understand the functional genetic variations in genetic diseases. In addition, the exome, being just a small fraction of the total genome, would be quite fast and affordable to sequence. This has largely been the guiding concept for this emerging technology, popularly known as exome sequencing.
Figure 1. Summary of the popular methods for capture of exons from DNA.
An informed consent would be required to be taken before the sequencing is performed. The consent should also encompass details of whether the patient would be willing to disclose and/or in times require to mask specific information in the report. A template for the consent is also available online.
Figure 2 . Schematic overview of GUaRDIAN Consortium
Figure 3. Summary of the steps required for sending samples for genetic studies as part of the GUaRDIAN consortium.
http://goo.gl/vdov1q . If you require a bound copy of the handbook, we would be happy to provide you a copy. We hope to reach out to a wider community of clinicians in the country and would also like to hear your comments which would immensely help us revise the handbook in future.
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