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Sequencing Breaks into the Clinic in 2011, but Ethical, Regulatory, and Technical Hurdles Remain


By Monica Heger

2011 will likely be recognized as the year that genome sequencing broke out of the research realm and moved into the clinic.

Driven by dramatically lower sequencing costs and the launch of benchtop sequencers by Illumina and Life Technologies, next-gen sequencing moved from being a research tool that could answer key clinical questions in specific cases to entering the broader clinical setting. Studies that made headlines in 2010 — such as an effort to find the cause of Charcot-Marie Tooth syndrome in Baylor's James Lupski, or the Medical College of Wisconsin's exome sequencing of a 6-year-old, which led to a diagnosis of severe inflammatory bowel disease — became almost commonplace over the course of 2011.

There are numerous signs pointing to the uptake of sequencing in the clinical market in 2011. A number of universities and companies began offering targeted sequencing panels to diagnose various diseases, with the clinical exome and whole genome close behind. Sequenom launched its noninvasive sequencing-based test to screen for Down syndrome in high-risk pregnancies and several firms are planning to launch similar tests in the coming year. Molecular diagnostic companies that have traditionally not used next-gen sequencing began moving into the field. And two efforts — one led by a large healthcare system in the US and the other by the government of the Faroe Islands — began exploring how whole-genome sequencing data can be incorporated into patients' health records.

While clinical sequencing has perhaps had its biggest impact in cancer — so much so that it will be the topic of a separate article in next week's Clinical Sequencing News — the technology is making strides in other areas, including Mendelian and complex disorders as well as maternal and fetal health.

Additionally, because the technology is advancing so rapidly, regulators have not been able to keep up, so the groups developing these tests have begun to address ethical, legal, and technical challenges on their own.

The National Human Genome Research Institute, a major source of funding for next-gen sequencing projects in the US, showed it is committed to clinical sequencing with the creation of two new programs, one of which will focus on Mendelian diseases and another that will study best practices for clinical implementation of next-gen sequencing (CSN 12/7/2011).

Over the last year, the question switched from asking whether it was even feasible to use NGS in the clinic to how sequencing should be used in this setting and what the best practices are.

From Targeted Panels to the Clinical Exome

In 2010, universities and companies launched the first next-gen sequencing-based multi-gene panels to diagnose diseases such as mental retardation, mitochondrial disorders, and congenital disorders. These panels sequenced up to around 100 genes known to be involved in the respective disease.

In 2011, however, groups and companies began moving beyond targeted panels to offering clinical exomes and even whole genomes. In some cases, insurance companies are even providing reimbursement for the tests.

A group led by Joris Veltman at the Radboud University Nijmegen Medical Center in the Netherlands, for instance, is conducting a 500-person pilot program designed to demonstrate that exome sequencing is more cost-effective than single-gene tests, particularly in cases where the diagnosis is uncertain (CSN 10/19/2011).

The team offers exome sequencing for a range of disorders, including deafness, blindness, movement disorders, mitochondrial disorders, and intellectual disability, and is being reimbursed €1,500 ($2,071) per patient for the trial by major Dutch insurance companies.

Following on its initial success in the Nic Volker irritable bowel disease case, the Medical College of Wisconsin and the Children's Hospital of Wisconsin have implemented a clinical whole-genome sequencing program for undiagnosed diseases, and as of August, it had identified disease-causing mutations in two additional cases, was still analyzing another two, and had five more cases in the pipeline (CSN 8/24/2011).

The group has even had two insurance companies agree to reimburse for the sequencing, because in these cases of very rare diseases, reimbursing for a slew of single-gene tests quickly becomes more expensive than whole-genome sequencing.

Whole-genome sequencing can be used not only to provide molecular diagnoses for these rare disorders, but it can also be used to help guide treatment, such as in the sequencing of the twins of Life Technologies' chief information officer Joe Beery (CSN 6/15/2011).

Several companies are now offering clinical exomes as well. Ambry Genetics launched a clinical exome sequencing test this year (CSN 10/5/2011) and GeneDx plans to begin offering its XomeDx test this month (CSN 10/19/2011). Both companies are offering the test through physician prescription to patients with severe undiagnosed diseases who have already been through a "diagnostic odyssey."

Aside from these firms, which have been in the next-gen sequencing space for some time now, several molecular diagnostic companies that had not previously used NGS entered the space this year.

Siemens Healthcare Diagnostics, for instance, is planning to convert a number of its genotyping assays to the Illumina MiSeq platform, beginning with its Trugene HIV assay, for which it will seek FDA 510(k) clearance (CSN 11/9/2011).

Maternal, Fetal, and Neonatal Health

Sequencing also made significant strides this year in the world of maternal, fetal, and neonatal health. Perhaps the biggest news was the launch of Sequenom's much anticipated MaterniT21 test to diagnose trisomy 21 in high-risk pregnancies (CSN 10/19/2011). The company has already processed its first samples and is pursuing reimbursement from insurance companies.

A similar test will soon be launched in Europe through GATC Biotech subsidiary LifeCodexx, which licensed Sequenom's technology.

Other companies such as Verinata Health and Aria are also developing sequencing-based trisomy 21 tests, which they plan to launch this year, and which will likely spark a patent dispute with Sequenom, which claims it holds exclusive rights to the test (CSN 12/21/2011 and 9/7/2011).

Sequencing assays are also being developed to test parents for carrier status and newborns for rare childhood diseases.

Children's Mercy Hospital in Kansas City, Mo., began a clinical trial of its assay to screen for 592 rare childhood diseases (CSN 8/9/2011), which it plans to launch broadly this year. The panel, which was originally developed by researchers at the National Center for Genome Resources, is being launched out of the hospital's Center for Pediatric Genomic Medicine and will initially be targeted at children with undiagnosed diseases, and eventually be offered as a pre-pregnancy carrier screening test.

Good Start Genetics also completed a validation study of its preconception carrier screening test for 22 disorders (CSN 10/26/2011).

Whole-Genome Sequencing for the Masses

The ultimate breakthrough in clinical sequencing, however, will be when whole-genome sequencing is used not only as a diagnostic tool, but as a screening tool among healthy individuals to help monitor health.

While most believe that this will not happen for another five to 10 years, some headway has been made. The Faroe Islands have embarked on a project to sequence all 50,000 residents. Dubbed FarGen, the project will begin with a pilot of 100 individuals and expand from there. Because the project will incorporate sequence data with patients' healthcare records, it could serve as a model for how to implement next-gen sequencing in a healthcare setting (CSN 11/2/2011).

In one of the first examples of a healthcare system adopting next-gen, the Inova Translational Medicine Institute signed an agreement with Complete Genomics for the sequencing of 1,500 genomes, including those of 250 babies born prematurely, 250 normal babies, and both parents of all 500 children.

While this pilot study will seek to identify prognostic, diagnostic, and therapeutic targets for preterm birth, it is also serving as a model for how whole-genome sequencing can be implemented within a healthcare setting, and is Inova's first step toward broader adoption.

Inova has already said that it would like to expand the project to 2,000 babies and then follow that cohort longitudinally to see whether the sequence data can identify markers of childhood disease and adult chronic disorders (CSN 9/14/2011).

The Fine Print: Legal, Ethical, and Technological Hurdles

Even though 2011 saw huge growth in the clinical sequencing field, before the technology can be routinely implemented in a clinical setting, a number of regulatory and ethical issues will need to be addressed. Currently, next-gen sequencing-based tests are being offered as lab-developed tests, usually in CLIA-certified labs, and are not regulated by the FDA.

The FDA, however, has indicated that it will consider regulating LDTs in the future, and in a sign that it thinks sequencing will have a major clinical impact, it held a day-long workshop in the spring discussing options for regulating clinical sequencing (CSN 6/29/2011).

While the FDA did not make any decisions or set a timeline for when, or if, it intends to issue guidance on the matter, the workshop addressed a number of questions, including the difficulty of setting standards for next-gen tests since the different platforms and technologies used all have different performance profiles and error rates.

Stakeholders agreed that moving forward, it would be necessary to have some sort of standard for next-gen tests, however, rather than basing criteria on a technology's accuracy, tests should be judged on their likelihood of obtaining a correct answer.

The Institute of Medicine also began to address the challenges of clinical sequencing, and hosted a workshop last summer highlighting these issues (CSN 7/27/2011).

But, with no clear guidance yet from the FDA or other regulators, groups looking to do clinical sequencing have had to come up with their own best practices, and have encountered a number of ethical dilemmas.

One main question that researchers struggled with this year is what to do in the case of unrelated findings. Because next-gen sequencing is such a powerful discovery tool, medically relevant information about a patient can be found that is unrelated to the original intent of the sequencing.

For instance, Gholson Lyon, a psychiatrist with the University of Utah, published a study in which he and his colleagues set out to use exome sequencing to study attention deficit disorder, but throughout the course of the study were informed that one of the volunteers had a case of anemia of unknown molecular cause. Because the team already had the patient's exome data, they were able to identify the cause of the patient's anemia, but the sequencing had not been done in a CLIA lab, nor was there a certified test with which to verify the results, although they were verified with Sanger sequencing (CSN 7/27/2011).

In a separate sequencing study led by Lyon, his team uncovered the causative mutation of a Mendelian disorder that leads to rapid aging and eventual death in male infants. Throughout the course of the study, one of the volunteers became pregnant with a son and wanted to know if she was a carrier for the disease. Because the study was not designed to allow for the return of results, however, Lyon was not able to provide the mother with that information, and her son was born with the disease (CSN 10/12/2011).

Groups have come up with a number of strategies to cope with the ethical issues of whether and how to return results to patients. Lyon, for instance, recommends that all human sequencing be done in a CLIA setting. The FarGen project will deal with the issue by not interpreting individual genomes until a specific question is asked by the physician.

Joris Veltman's group at Radboud University, which is offering clinical exomes, will filter sequence results for genes related to the specific disease for which they are testing.

Aside from the ethical and regulatory issues, there are still a number of technological hurdles in clinically interpreting genomes.

Variant databases, which were designed for research purposes, have been found to be riddled with errors. When Stephen Kingsmore and his team from the NCGR were validating their rare childhood disease assay, they found that as many as 27 percent of the variants cited in the literature as disease mutations were either misannotated or common polymorphisms.

As a result, a number of groups that are offering clinical sequencing have begun to develop their own databases, including the Partners HealthCare Center for Personalized Genetic Medicine (CSN 7/6/2011).

A number of companies have also sprung up to fill the niche of clinical genome interpretation, including Personalis, founded this year by a team of researchers from Stanford University; and Omicia, which launched its VAAST tool this year to find disease-causing genes from sequence data.

While clinical sequencing saw explosive growth this year, it is these remaining regulatory, ethical, and technical issues of interpretation that will likely be the focus of much debate and study in the coming year.

Have topics you'd like to see covered by Clinical Sequencing News? Contact the editor at mheger [at] genomeweb [.] com.