Blog @ Illumina
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Babies, babies, and more babies

Linda Seaton
| Oct 24, 2012

Contrary to the news reports that couples are putting off having children, there seems to be a baby boomlet occurring in San Diego. So many people I know are about to become parents, from friends, to neighbors and coworkers. It seems that even researchers have babies on their minds, with several recent papers focused on sequencing of neonatal and fetal genomes.

childrens mercy kcTime is of the essence in diagnosing and treating critically ill newborns. Often the cause is genetic, but the disease presentation is so undifferentiated at birth that it’s difficult to diagnose. To provide potentially life-saving genetic information to clinicians, a pilot clinical study by researchers at Children’s Mercy Hospital in Missouri applied whole-genome sequencing (WGS) to diagnose genetic diseases of neonates in intensive care units. Employing a new approach, called STAT-Seq, researchers combined WGS on a HiSeq 2500 system with a bioinformatics platform they developed that refines genome analysis to only those regions harboring mutations responsible for monogenic diseases. It yielded results in less than two days compared to the four to six week turnaround of current genetic analysis methods. The accuracy and speed of this new approach could save lives, providing clinicians with information to quickly diagnose and treat neonatal genetic disorders.

Sequencing the DNA of a newborn is one thing, sequencing the DNA of a fetus is quite another. One of the biggest hurdles—identifying a non-invasive way to access fetal DNA—was overcome in the last few years with the refinement of a method that captures cell-free DNA floating in maternal plasma. Together with next-generation sequencing, this method is the foundation of several prenatal screening tests to detect major abnormalities in the fetal genome, such as trisomies. However, it doesn’t enable the differentiation of fetal DNA from maternal DNA at the high resolution needed to accurately identify inherited alleles or de novo muations.

That issue was solved by a research team in the Department of Genome Sciences at the University of Washington, which developed a haplotype-resolved genome sequencing method that combines the throughput of next-generation sequencing with the contiguity information provided by large-insert cloning. I spoke with doctoral candidate Jacob Kitzman, learning more about the method and how they used it and the HiSeq 2000 system to determine the whole-genome sequences of two fetuses, one at 18 weeks and the other at 8 weeks gestation. The team successfully predicted fetal inheritance at 2.8 × 108 parental heterozygous sites with 98.1% accuracy.  That’s truly a remarkable feat. It’s clear that process improvements in the haplotype aspect of the method will need to be made before it can be routinely used in a clinical setting. And they’re working on increasing the coverage and refining the analysis to improve the method’s accuracy. They’ve already added the MiSeq to the workflow, using it to quickly verify the percentage of fetal DNA in the maternal blood sample sequence libraries, prior to sequencing on the HiSeq. It may still be in its infancy, but whole-genome fetal DNA sequencing just took a huge step forward.