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Next-Gen Sequencing Gets a Fix on Disease

Article Author: Neil McKenna
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Recent years have seen rapid advances in the capacity of molecular biological techniques to simultaneously interrogate multiple targets on omics platforms.

While these techniques are well established in basic research, they have more recently gained a foothold in clinical diagnostics, with an increasing number of laboratory tests incorporating some type of high-throughput or global-scale molecular analysis. Of these techniques, the one that arguably has the greatest potential to revolutionize our approach to diagnosing disease and tailoring therapies is next-generation sequencing (NGS).

NGS, which refers to a constellation of techniques in which DNA or RNA fragments are sequenced in parallel, offers significant increases in speed, scalability, and resolution over traditional sequencing methodologies. Testament to the considerable interest in NGS is the increasing number of conferences exclusively devoted to the topic.

One such event, GTCBio’s “Next-Generation Sequencing” conference, was recently held in San Diego. Presenters showcased the application of NGS-based diagnostic platforms in a variety of clinical settings.

Preimplantation Genetic Screening

Varied genetic prenatal conditions impact pregnancy and fetal development. Accordingly, preimplantation genetic screening (PGS) has emerged as an important clinical tool for identifying chromosomal aberrations.

Traditional prenatal screens have a number of limitations. Some screens, such as amniocentesis or chorionic villi sampling, are invasive; others, such as ultrasound or biochemical screening, are less invasive but limited in their sensitivity and specificity.

“In contrast to these techniques, noninvasive PGS-based on NGS has both superior detection sensitivity and specificity for chromosomal abnormalities,” said Keith Jones, Ph.D., vp of development at Illumina. “The Illumina verifi® test detects greater than 99% of all true-positive cases and has a cumulative false-positive rate of <0 .2="" br="">
The verifi test uses sequence information from across the genome. This approach, Dr. Jones suggested, allows for the rapid adoption of additional tests that may find abnormalities not readily detected using traditional screening approaches. Such abnormalities include sex chromosome aneuploidy, microdeletions, trisomy 9, and trisomy 16.

Approximately 1.3 million in vitro fertilization (IVF) procedures are performed globally each year; however, only 25% of the procedures meet with success. The low success rate is usually attributed to complicating factors associated with advanced maternal age and chromosomal aneuploidy in the embryo.

“The aim of PGS in the IVF setting is to select chromosomally balanced embryos during the IVF process and ensure that only euploid embryos—those with a normal number of chromosomes—are implanted during IVF procedures,” explained Dr. Jones. He added that PGS has been shown to improve implantation success rates and reduce the number of high-risk pregnancies associated with multiple egg transfers.

In Illumina’s VeriSeq™ PGS platform, genomic DNA from a single cell is amplified and sequenced to provide a genome-wide view of the copy number state of the embryo. The protocol takes less than a day and allows multiplexing of up to 24 samples per sequencing run, translating to an increased likelihood of identifying a viable embryo and decreasing the time between biopsy and an answer. “The broad dynamic range derived from the sequencing data makes interpretation clear with a high degree of confidence,” Dr. Jones asserted.

Testing for Minimal Residual Disease

“The overarching theme in the NGS molecular diagnostics space is that robust clinical validation is a must,” said Martin Moorhead, Ph.D., vp of computational biology and software development at Sequenta. The company’s LymphoSIGHT platform is an NGS-based immune repertoire analytical solution that combines multiplex PCR assays and informatics algorithms to interrogate rearranged immunoglobulin and T cell receptor genes.

“Our PCR process targets the CDR3 region and the immediate surrounding sequence, yielding amplicons that are typically around 150 base pairs in length, which is ideal for NGS analysis,” Dr. Moorhead pointed out. In the assay, sequencing of rearranged B or T cell receptor gene amplicons from patient lymphocyte samples allows for an absolute quantification of the number of each clonotype—cells all sharing the same rearranged receptor sequence in the original sample.

“The first clinical product we developed using the LymphoSIGHT platform is the ClonoSIGHT test for measuring minimal residual disease (MRD) in patients with blood cancers, including diffuse large B cell lymphoma, multiple myeloma, acute lymphoblastic leukemia, chronic lymphocytic leukemia, and mantle cell lymphoma,” stated Dr. Moorhead. MRD refers to cancer cells that may remain in the body of a person with lymphoid cancer after treatment, and is the leading cause of relapse in this condition.

Testing for MRD can help determine whether treatment has been successful, provide important information about patient prognosis, and help guide additional treatment decisions. At its essence, the ClonoSIGHT assay compares cancer cell DNA sequences generated using the LymphoSIGHT platform in a diagnostic sample with those in follow-up samples to determine the presence of residual cancer cells.

“ClonoSIGHT test results, which are generated in seven days using our CLIA-certified, CAP-accredited laboratory, are provided in a simple, actionable report,” added Dr. Moorhead. “[The report] shows a patient’s MRD status and level as well as MRD trends over time.”

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Data source: Stork Fertility Center 2013 data
Stork Fertility Center Stork Fertility Center Author


  1. In the diagnose of some children diseases, people start to discard the traditional methods of diagnose gradually, inclining to the next-generation sequencing technology. And many sequencing companies have got the point.

  2. Instead of taking the risks after age 37 the ladies should understand the peak fertile age is always between 20 and 25. IVF babies are more likely to be short, fatty, sub-fertile... the list very long.