While genetic diseases pose the single biggest source of infant mortality in the U.S., many of these disorders are so rare, and little understood that an accurate diagnosis could take weeks or months. Some babies don’t have that much time. For others, the battery of tests that tend to be ordered adds to their suffering and often still ends with no diagnosis. Hope for these children and their families may be coming in the form of DNA sequencing, or screening of a patient’s genetic code for tell-tale aberrations. Right now, DNA sequencing is rarely used in a clinical setting, partly because of cost and because insurance rarely covers it. But recent studies are raising hopes that, due to technological advances and re-engineering of processes, DNA sequencing of acutely ill newborns may be moving closer to mainstream clinical practice, allowing neonatal physicians to make diagnoses much faster—sometimes in a matter of days—to administer effective treatments sooner, and to cut the cost of care. By making it more feasible to use DNA sequencing, especially early in the process, physicians can skip over the “million-dollar workup we’ve been doing,” says Tracy Trotter, co-chair of the American Academy of Pediatrics’ Council on Genetics. “Now we’re talking about one test.”
The Problem of Diagnosis
About 3% of babies born in the U.S. each year have genetic diseases, often caused by random mutations not passed down by parents, according to the Centers for Disease Control and Prevention. But diagnosing a new-born is challenging because many symptoms aren’t pronounced, or are similar to symptoms for a wide range of maladies. In such situations, physicians typically order a succession of consultations and specialised exams, including MRIs, EEGs and other procedures. This often takes up to three weeks. If the underlying illness isn’t discovered and the baby is still struggling, doctors often turn next to targeted gene tests to look at a suspect group of genes and whether a mutation exists there. Gene panels, for instance, focus on a few dozens to a few hundred genes. They also take two or three weeks before results are known.
DNA sequencing, by contrast, looks at a far bigger genetic picture. There are two types of sequencing currently available to physicians involved in neonatal care: whole-genome sequencing, which, as its name implies, reads all of an individual’s DNA, and whole-exome sequencing, which looks only at the nearly 2% of the genome—known as the exome—where instructions for building the body’s proteins are found. The exome is where most genetic research has occurred, and where most diseases have been found to date. But some genetic diseases can still originate in the other 98%, and thus go undiagnosed unless whole-genome sequencing is performed. Whole-genome sequencing also is expected to help researchers identify new inherited diseases. Whole-genome sequencing tends to cost much more than whole-exome, but prices of both are declining rapidly. Commercial labs typically charge from $3,000 to $10,000 for a whole-exome sequencing of a “trio” of baby and parents, including the interpretation needed for a diagnosis, and whole-genome sequencing tends to cost about 50% more.
A team of researchers at Rady Children’s Institute for Genomic Medicine in San Diego, meanwhile, has conducted a study suggesting that whole-genome sequencing can be performed in a matter of days instead of weeks—and with better results than diagnostic tests currently favoured for babies in intensive care. In a paper published in NPJ Genomic Medicine in April, the researchers reported the results of a study involving 42 acutely ill infants whose symptoms had previously eluded diagnosis. Whole-genome sequencing provided a definitive diagnosis within days for 43% of the cases, and immediately changed the medical treatment for 72% of those. The outcomes: 11 babies potentially avoided serious illness and long-term disabilities, and one had a greatly increased chance of surviving. For the sequencing to result in treatment changes for nearly a third of the cases looked at “is remarkable,” says Dr Trotter of the American Academy of Pediatrics, who is also a paediatrician in San Ramon, Calif. That’s more than five times “anything we’ve done through any other testing mode,” says Dr Trotter, referring to the range of diagnostic tests given to acutely ill babies who could have a genetic disorder. To speed up the process, Rady Children’s uses the fastest, $1 million sequencing machines. The researchers in the study also reorganised the workflow from top to bottom. For instance, the nurse who draws the baby’s blood carries it directly across the street to the lab, where the scientists are waiting for it. Once the DNA sample is prepared, it goes straight onto the sequencer, whereas other labs wait to batch samples for efficiency.
The Rady Children’s study, part of a broad project funded by the National Institutes of Health to investigate potential applications of genomic sequencing in the new-born period, also suggested that dramatic cost reductions can be achieved using whole-genome sequencing. While the cost of the sequencing totalled $675,000 for the 42 babies in the study, for just six of the babies (for whom similar control cases could be found), total costs, based on varied assumptions, were cut by a range of $800,000 to $2 million, according to an outside panel of neonatologists and medical geneticists. Big cost reductions thus can be achieved by shortening stays in intensive care, eliminating tests, procedures, specialists visits and even surgery. Even with its narrower scope, whole-exome sequencing supplied impressive results in another study, published in JAMA Pediatrics in December. For 278 critically ill infants whose diagnosis had been unknown, whole-exome sequencing produced a diagnosis for 37% and immediately influenced medical care for half of those. For urgent cases sequencing was done in less than two weeks, in contrast to the usual, time-consuming list of diagnostic procedures. The researchers, from Baylor College of Medicine in Houston, said the early treatment that resulted included lifesaving operations such as transplants. With effective medication, one baby stopped having seizures, which can cause lasting neurological damage.
Rady Children’s complete-genome research is continuing, and six neonatal intensive-care units around the U.S. have signed up to participate. Dr Stephen Kingsmore, chief executive of Rady Children’s Institute for Genomic Medicine, says he believes that in five years DNA sequencing “will be standard of care for acutely ill infants in the U.S., a commercial test that everyone can order.” Among the steps that need to happen first: expanded research showing improved care for large numbers of patients. More data will be crucial, says Dr Trotter. “If they can nail down and prove the savings, get the third-party payers online, that big jump in treatment changes is going to make it a pretty easy sell” for physicians. “Once you’re involved in one case that saves a life or saves a brain,” he says, “you’re so affected that you’re sold. That’s what we live for.”
Credit: Dana Wechsler Linden for The Wall Street Journal, 28 May 2018.