At the Beyond the Genome conference in Washington, DC, this week, researchers discussed the various ways they use next-generation sequencing techniques, particularly exome sequencing, to discover, among other things, gene variants that may be associated with, or cause, disease. Joris Veltman from the Nijmegen Centre for Molecular Life Sciences in the Netherlands discussed a de novo approach to find mutations associated with mental retardation and intellectual disabilities. The dogma that says inborn diseases are inherited is wrong, he said, and focusing on inherited genetic variation does nothing to uncover the causes of diseases like autism or schizophrenia, which often occur sporadically. CNVs, however, have been associated with n intellectual disabilities, and when that research was applied on a large scale, it was found that CNVs are frequent and occur throughout the genome in the intellectually disabled, Veltman said. That started him and his colleagues thinking about de novo mutations as possible causes for some of these diseases. If this is the case, he added, then the mutational target itself can determine the frequency of the disease, depending on its size. If the mutated gene is small, the result is a rare disorder. But if the mutated gene is big, the disorders occur more frequently. Veltman and his team conducted next-generation sequencing of patient-parent trios to detect de novo mutations, and he said many researchers are now doing similar studies, which can present both "biologically useful and clinically actionable" information on possible causes of intellectual disabilities. De novo mutations may be a common cause of intellectual disabilities, and family-based exome sequencing allows researchers to identify them, he said.
In a separate session, Stephen Kingsmore of Children's Mercy Hospital in Kansas City, Mo., discussed the possible clinical applications of next-gen sequencing in a children's hospital setting. Exome sequencing is helping to reclassify many subsets of the thousands of Mendelian disorders that affect children, and is also helping to find the genetic basis of these diseases. But testing for these diseases lags decades behind molecular knowledge of them, and there are only a couple of hundred tests in existence, despite that the causes of more than 3,000 diseases are already known, Kingsmore said. Today, he added, Sanger sequencing in a clinical setting is done one patient at a time, costs thousands of dollars, and has a 50 percent success rate in determining what's wrong with a patient. The next step is what Kingsmore called "Mendelian genomic medicine" — a combination of diagnosing Mendelian diseases in children at presentation, newborn screening, preconception carrier testing, fetal diagnosis and treatment, and pharmacogenomic testing before treatment. With the cost of sequencing falling rapidly and the speed of the technology increasing, using next-gen sequencing techniques in the clinic will soon be very cheap, Kingsmore said, especially when the tests are done in "batch mode" for many patients at once. And the faster turnaround time will mean that more patients are diagnosed, he added.