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2-Day, $13K Sequencing IDs Genetic Diseases in the NICU

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By Anette Breindl
Science Editor

According to the March of Dimes charity, 10 percent to 15 percent of all newborns are admitted to the neonatal intensive care unit (NICU). Many of those babies suffer from genetic disorders. In fact, Stephen Kingsmore told reporters at a press conference, at his hospital – Children's Mercy Hospital in Kansas City – "the leading cause to admission to a neonatal intensive care unit is an illness that is likely to be genetic."

For several reasons, diagnosing such genetic disorders is often a race against the clock. Even as such illnesses can progress very rapidly, they are not trivial to diagnose. Diagnosis is done by sequencing a candidate gene based on the symptoms a baby displays. But those symptoms can often be consistent with a number of different disorders, and not every baby will display every symptom.

Those two phenomena, known as genetic and clinical heterogeneity, respectively, "are two situations that really stump doctors" in identifying the right gene to sequence, Kingsmore said – assuming they knew about that gene in the first place. Some genetic disorders are easy to identify for experts, but so rare that they are simply not on the radar of the average practicing physician, who might well never see even a single case over the course if his or her career.

As a result, most often, "from a practical standpoint, babies died or else got better and were discharged home" in the time it could take to get a diagnosis.

In the Oct. 4, 2012, issue of Science Translational Medicine, Kingsmore and his team described a method that enables such diagnoses to be made within 50 hours, at a cost of roughly $13,000 – or less than the cost of two nights in the NICU.

Because it winnows down the genes that are confirmed, the system also avoids one of the current headaches of whole-genome sequencing, namely, what to do with incidental findings. (See BioWorld Insight, Oct. 1, 2012.)

"It is now feasible to decode an entire genome and provide interim results back to the physician in two days. We think this is going to transform the world of neonatology," Kingsmore told reporters. "Up until now, they have really had to practice medicine blindfolded."

The authors used a high-speed sequencing method by Illumina Inc. to sequence the whole genome of critically ill infants. Such sequencing takes about 25 hours – but usually, expert analysis of candidate genes, which needs to be done one at a time, takes weeks.

The team winnowed down the number of genes that needed expert review through using what they called symptom- and sign-assisted genome analysis (SSAGA). When physicians enter symptoms into the SSAGA program, it spits out the genes that could be mutated to produce those symptoms. While any one symptom is usually consistent with mutations in many diseases, the overlap between several symptoms can winnow down the number of genes that need to be reviewed individually. For example, one patient had low muscle tone, developmental regression and leukodystrophy, or problems with the myelin sheath that insulates neurons. While 352 genes are currently known to be possible causes of one of those three symptoms, only nine genes are potentially a cause of all three.

The hope offered by the new approach, it should be noted, often ends up being the sort of grim, tattered hope that is typically available to the survivors of natural disasters. To wit: each of the seven babies whose genome was analyzed for the study is now dead.

That is not itself surprising for a research study on severe and rapidly progressing diseases. But the larger statistics of fatal genetic disorders are themselves sobering.

Causal genes have been identified for roughly half of the estimated 7,000 known single-gene disorders. And some form of treatment exists for about 500 of those 3,500, and fewer than 100 of those offer a markedly better prognosis with early treatment.

Kingsmore said, however, that the benefits of a definite diagnosis are not confined exclusively to those babies where that diagnosis comes with a treatment.

Such a diagnosis, he said, "still can have tremendous benefits" for a family.

Some of those benefits lie in what it allows them to avoid. A diagnosis, even as it ends hope, also means no endless search for an answer. And "it allows the families to make deliberate decisions" on how long and how intensively treatment should continue.

Sometimes, such a diagnosis allows babies to be moved out of the ICU, "to a regular bed, where there can be some bonding with the mother, and where the family can grieve and say goodbyes. . . . One of the biggest surprises to me was that families we give a diagnosis to where there is no treatment are often phenomenally grateful."