How Genome Sequencing is Revolutionizing Clinical Diagnostics, from the ISMB Conference
Reporter: Aviva Lev-Ari, PhD, RN
08WednesdayAug 2012
Written by Filipe J. Ribeiro in Events
Tags
computational biology, exome sequencing,Huntington’s disease,molecular biology, whole-genome sequencing
Filipe J. Ribeiro is a Bioinformatics Scientist at the New York Genome Center.
Recently, I attended the 20th Annual Conference of Intelligent Systems for Molecular Biology (July 15-17, 2012), organized by the International Society for Computational Biology. The conference focuses on the application of computer science, statistical, and mathematical methods to biological systems. I also attended the High Throughput Sequencing Methods and Applications (HiTSeq) satellite meeting (July 13-14, 2012). There, the speakers addressed the opportunities and challenges presented by the availability of the increasingly large genomic datasets from next-generation sequencing.
Many topics were discussed during the two days of HiTSeq, such as new data-analysis methods for RNA sequencing data, methods for improving de novoassemblies, and sequencing-data compression. What impressed me the most were the keynote addresses given by Dr. Stanley Nelson, from the Jonnson Comprehensive Cancer Center at UCLA, and Dr. Gohlson Lyon, from Cold Spring Harbor Laboratory. Both speakers focused on how whole-exome andwhole-genome sequencing are on the verge of revolutionizing clinical diagnosis of genetic disorders and what challenges need to be addressed before sequencing penetrates the clinic.
Dr. Nelson’s talk centered on the use of exome sequencing in the clinical diagnosis of genetic conditions. He presented a few case studies of young children with various rare developmental delays. Rare conditions can be hard to diagnose, and often times numerous tests need to be performed before a conclusion is reached, if a conclusion is reached at all. Also, some conditions are caused by a variety of different mutations to a single gene. These are harder to detect with conventional targeted genetic testing, which relies on known mutations. With exome sequencing a single test is performed; that one test identifies all coding mutations, known and unknown, simple and complex. Even when there is no smoking gun in the large set of mutations typically found in any single individual, the genotype can be reanalyzed at a later point, in light of new research findings.
However, challenges in genomics-based diagnosis still remain. Dr Nelson reports that in roughly 50 percent of cases studied clinically at UCLA, a known causal mutation is found. In 25 percent of cases, a novel genetic mutation is identified that is potentially causal, and in the remaining 25 percent of cases no conclusion can be drawn. Because of the large number of novel mutations that are present in any single individual’s genome, establishing causality of novel variations is often very hard, and care must be taken when interpreting results in order to avoid false positives. To minimize the risk of misdiagnosis in a clinical setting, it is fundamental to have a board of scientists and clinicians to review the conclusions of sequencing tests to ensure their validity.
Another challenge is what to do with secondary or unrelated findings—for example when a patient comes in with a set of symptoms indicative of one condition, and the genetic test finds a different one that is unrelated and asymptomatic. Some conditions (like Huntington’s disease) have no cure, and the patient might not want to learn about any diagnoses that are not actionable. A great deal of care must be taken both before and after genetic testing takes place so that patients understand the risks and the meaning of results.
On a slightly different note, Dr. Lyon focused on the ethical difficulties of returning research-grade results on genetic disorders to study participants. As an example he presented the case of a family that carries a genetic mutation that is fatal in boys at a very early age. A mutation was identified and shown to be causal in a research setting. The ethical dilemma for the researcher is: if one of the women in the family is pregnant with a boy, should she be informed of her carrier status? Research standards are not at the same level as clinical ones, and research results can at times be wrong.
It is not an easy question. Dr. Lyon’s suggestion is that research-grade whole-genome and whole-exome sequencing of study participants should be conducted under the same CLIA-certified standards as clinical tests, with the goal of returning research results to the study participants. Again, counseling and education of study participants regarding the risks and benefits of genetic testing are critical.
One barrier to the adoption of sequencing in a clinical setting is the fact that insurance companies do not cover the costs of whole genome sequencing as they are not yet convinced of the benefits. But that attitude will hopefully change as sequencing costs keep decreasing, and success stories abound. Soon it will be clear that genome sequencing is cost effective in disease diagnosis, prevention, and treatment. Also, for the most part genome sequencing is done only once in a lifetime, and therefore it is not a repetitive cost. (Cancer is an exception; one might want to sequence the cancer cells to identify which specific mutations are driving the tumor and to what drugs the tumor might respond.)
In summary, both speakers painted a picture of how whole-genome and whole-exome sequencing is quickly proving itself as a revolutionary tool in the clinic. Clearly challenges remain: test interpretation must be done carefully, ideally by a board of both scientists and clinicians, and strict CLIA standards should be in place, even in a research setting. But it is certainly clear that next generation sequencing will play an increasingly significant role in the clinic, and, most importantly, in our health.