Sequencing the first human genome was a massive undertaking. The project cost $1 billion and lasted 13 years. But genetic technologies have progressed dramatically, and a team from the Rady Children’s Institute for Genomic Medicine recently sequenced a genome in 19.5 hours, marking the feat with a Guinness World Record.
Standard whole genome sequencing currently takes two to eight weeks. Faster sequencing isn’t necessary for all patients, but it can be tremendously helpful for those in intensive care who suffer from rare genetic disorders. A speedy diagnosis can change the medication or procedures that a doctor orders for patients and add critical time for treatment.
“A lot of babies with genetic diseases will die pretty rapidly if they’re not diagnosed, or else they’ll suffer organ damage. Today, that’s just what happens,” says Stephen Kingsmore, president and chief executive officer of Rady Children’s Institute for Genomic Medicine. “These babies get every test that can be performed as quickly as possible, but unfortunately their leading causes of death are genetic illnesses.”
The importance of rapid sequencing stems from the difficulty of diagnosing rare conditions. There are over 8,000 rare genetic disorders, so it’s incredibly difficult for a physician to identify the correct disease, Kingsmore says. Different diseases can also produce identical symptoms, which can prevent doctors from detecting the underlying cause and ordering the appropriate treatment.
These underlying diseases are often treated in remarkably different ways. For example, Kingmore’s team has used genetic diagnosis to differentiate between various forms of epilepsy, all of which present as seizures in children. Newborns with Ohtahara syndrome are treated with the drugs phenytoin or carbamazepine, but those with pyridoxine-dependent epilepsy require vitamin B6 and the amino acid arginine while restricting the consumption of the amino acid lysine. If a doctor does not provide the correct treatment early enough, a sick infant may not survive.
“If you go to a doctor with a headache he may give you Advil. If you go to a doctor with a headache caused by a very rare condition, and he knows what the condition is, he may give you a completely different treatment,” Kingsmore says. “And that’s the case for seizure disorder, where there are over 1,000 genetic diseases that can cause seizures in a baby.”
Rare conditions affect a large number of American babies. There are 10,926 births on average each day in the U.S., according to the March of Dimes, an organization devoted to maternal and infant health. Of those births, 437 — or about 3 percent — will have a genetic disease, Kingsmore says. These numbers likely underestimate the true prevalence, since not all babies undergo genetic testing, he says.
Rapid sequencing also has implications outside of the neonatal ward. It may be helpful in making diagnoses in adults who fall ill from genetic disorders that manifest later in life. Swifter sequencing may also benefit certain cancer cases, says Arupa Ganguly, director of the Genetics Diagnostics Laboratory at the University of Pennsylvania. If a tumor is sequenced quickly and a targeted therapy is available, intervening earlier could yield a better chance for patient survival.
But Ganguly is skeptical that rapid sequencing will quickly become widespread, particularly due to the time-consuming stage of analyzing the sequenced data to deliver a definitive diagnosis. “These are proof of principle experiments. In real life, they don’t work as efficiently,” she says.
Wider implementation of rapid sequencing faces numerous hurdles, according to Madhuri Hegde, executive director of the Emory Genetics Laboratory: initial investment in equipment, obtaining infrastructure and expertise, educating physicians, updating hospital policies, gaining insurance coverage, and performing accurate analysis and interpretation.
In terms of overall cost, however, rapid genome sequencing will likely save the healthcare system money, Hegde says. “The cost associated with an individual being in the neonatal intensive care unit is enormous compared to doing genomic medicine.”
But whole genome sequencing is not the only test to diagnose genetic illnesses. A more common test is whole exome sequencing, which only looks at regions of DNA that contain instructions for building proteins. The collection of these regions, called the exome, represents just 1 to 2 percent of the genome. Therefore, exome sequencing has key advantages over whole genome sequencing, such as speed and cost.
Exome sequencing takes three to four weeks, while genome sequencing takes two to eight weeks depending on the lab, Hegde says. For urgent cases, a lab can usually complete exome sequencing in three to four days and genome sequencing in seven to 10 days. Exome sequencing is also much cheaper, she says. It costs $400 to $500 to sequence an exome, and $1,000 to $1,200 to sequence a genome. And these estimates exclude operational costs like overhead, labor, analysis, interpretation, report writing, and regulatory compliance, which drive up the final price. Insurance coverage is more common for exome sequencing, but reimbursement is inconsistent overall, Hegde says. Kingsmore’s rapid sequencing test, for example, is not currently covered by insurance.
But Kingsmore is hopeful that rapid genome sequencing will expand in order to fight rare diseases. The Rady Institute has already established partnerships with hospitals in California, Minnesota, and Colorado, to offer the test to patients in various clinical trials. “Babies have days and weeks to live,” Kingsmore says. “You’ve got 8,000 diseases, and you have to pick one or two. It’s like playing the lotto.”