Rapid Genetic Testing May Have Spared This Baby From Death
— Whole-genome sequencing delivered diagnosis in record 13 hours; treated with thiamine
For an infant with seizures, every passing hour risks more harm to the newborn’s brain.
That’s why this story from Rady Children’s Hospital in San Diego is so inspiring, not just for parents and their children, but for doctors and geneticists.
It shows the huge progress since the start of the Human Genome Project 30 years ago, not only in faster sequencing of 3.2 billion base pairs, but the ability to convert that information into a diagnosis. This case, which was published in the New England Journal of Medicine, is one that was easy and inexpensive to treat.
The ordeal began one Sunday night in October 2020 when a frightened couple took their 41-day-old child to Rady’s emergency department (ED) because he wouldn’t stop crying. The same thing happened to their newborn daughter 10 years earlier, before genetic testing was as advanced. The sister deteriorated rapidly and died before her first birthday. Would her brother have the same dire course?
‘This Is Why I Chose Genetics’
“This [baby] is exactly the reason I chose biogenetics,” said Anna-Kaisa Niemi, MD, who is both a Rady neonatologist and metabolic geneticist. “You always try to find the defect and the diagnosis and if you do, you’re able to start treatment fast. But it’s never happened this fast before.”
Late that October night, a head CT showed worrisome changes and an MRI revealed concerning white patterns in the infant’s basal ganglia. The ED team transferred the baby to the hospital’s NICU. When Niemi arrived Monday morning, the child was still crying.
“It wasn’t a hungry cry, or ‘my diapers are dirty’ cry, or even ‘I have a broken bone’ cry. It was non-stop, inconsolable crying, like something is very wrong in the brain,” Niemi told MedPage Today. “I don’t want to say scary, but it was very alarming to me. I knew we needed to figure it out right away.”
A physical exam revealed downward eye deviation, and the parents disclosed they are first cousins, more hints for a possible genetic abnormality. An electroencephalogram identified brain seizures.
Mallory Owen, MBChB, a pediatric neurologist who then was working with the affiliated Rady Children’s Institute for Genomic Medicine (RCIGM), described what happened next.
“We got a call from the [hospital] medical director who said we have a baby in the NICU who I think might really benefit from having this research protocol, ‘ultra-ultra’ rapid whole genome sequencing,” said Owen.
There are some 1,500 genetic diseases associated with epileptic encephalopathy with similar or identical symptoms but very different treatments, Owen said.
To attempt to figure out which one it could be, a blood sample was drawn by 4 p.m. Monday and sequencing began at 7:23 p.m. It was completed by 6:30 a.m. Tuesday, according to a timeline prepared by Owen, lead author of the case report.
By 7:24 a.m. Tuesday, the in-house sequencing process was aided by Rady’s partners, Illumina, which has developed DNA PCR-Free Prep, and Alexion Pharmaceuticals, whose scientists helped narrow the list of variants to match the infant’s symptoms.
One in a Million
The result, 10 minutes later, revealed the boy had autosomal recessive thiamine metabolism dysfunction, syndrome 2, (THMD2) a defect in the mechanism responsible for transporting thiamine from the blood to the brain. But lucky for him, oral supplements of two over-the-counter vitamins, thiamine and biotin, resolved the problem.
THMD2 is extremely rare, occurring in an estimated one-in-a-million babies, according to the institute’s medical director, David Dimmock, MD. It’s a two base-pair frameshift, which Owen described as like a line of text in which the last two letters of one word are shifted into the next word, “and suddenly all the words don’t make sense because the spaces between the words are in the wrong places.”
It is likely that because the mutation is homozygous, the child inherited one copy from his mom and one from his dad, who each had the same mutation because they are related, she said.
By 12:13 p.m. Tuesday, vitamin tablets were crushed, added to liquid in appropriate dosage and administered to the infant through a feeding tube. Six hours later, his crying, seizures and irritability had resolved and as of June 14, have not returned. “The baby looked completely different,” said Niemi. “It’s unbelievable how fast (the vitamins) worked.”
Time will tell if the baby, now 9 months old, will have permanent damage from his first 5 weeks of life. Owen acknowledged some signs of delayed development that could resolve in time, though it’s too soon to tell. “No baby with this particular disease has been treated this early,” she said.
But without this diagnosis, Owen is confident the boy would follow the path of his sister, who had the same seizures and “basically made no developmental progress from 2 months of age to the time of her death.”
RCIGM had been working on developing a way to sequence the entire genome faster for 6 years. At commercial labs nationally, standard whole-genome sequencing can take weeks to identify a culprit sequence variant.
Like several other genetic projects around the globe, the institute has developed faster techniques: a “rapid” method that takes less than a week and an “ultra-rapid” protocol that averages between 30 and 50 hours. Still experimental, however, is this 13.5-hour process, nicknamed “ultra-ultra-rapid” by the team.
Time is of the essence in newborns, and a week or two delay can be fatal. During that time, the clinician has already administered ineffective treatments that may even have caused harm. “There could already be permanent brain damage, and when that happens, it’s irreversible,” Owen said.
Marc Williams, MD, president of the American College of Medical Genetics and Genomics, who heard about the case on social media, called Rady’s latest sequencing speed “transformative,” potentially saving many children from conditions such as intellectual disability or cerebral palsy.
For most hospitals today, if a clinician orders a sequence for a child with a suspected abnormality, it would be sent to an outside laboratory and take anywhere from 1 to 3 weeks to get back, and even then, may not give enough specific information.
“One could argue the difference between 50 hours or 30 hours or 13 hours isn’t all that big of a deal,” he told MedPage Today. But the bigger deal, he said, is now we have “a child who has a chance at a normal outcome, as opposed to either death or severe disability if we did things the way we’ve always done them.”
Asked if there is a kind of race going on among geneticists to see who can beat the clock, Williams said Rady’s team keeps trying to beat itself. “They’re pushing the limit to show how fast we can do this, in some ways, like a sprinter who sets a world record, but now says I think I can go faster.”
The institute now does sequencing for a network of 60 other children’s hospitals in the U.S. and Canada. Since last October, it has performed ultra-ultra-rapid sequencing on two other babies and got a diagnosis for one of them, a rare mitochondrial disease. That case is being written up for publication.
Does Rady see itself as the go-to institute for hospitals with patients suspected of having treatable genetic conditions?
Mallory said that becoming a “center of excellence” for whole genome sequencing is one of its aims, especially for NICU babies. But, she said, “rapid sequencing needs to be something that is not led by a single center. It’s a huge project, with huge massive data requirements, and really should be pushed forward by a large assortment of institutions, of which Rady is one.”
Rady’s ultra-ultra-rapid sequencing is still in the research phase. It was funded by numerous federal grants to its president/CEO, Stephen Kingsmore, MBChB, DSc, and did not cost the family.
Currently, the Rady institute’s cost is around $10,000 for standard sequencing, although this varies case by case. When it’s ready and has received required approvals, the ultra-ultra-rapid will cost much more.
That’s why bills were recently introduced in the U.S. Senate and in the California legislature to cover the cost.
Sen. Susan Collins (R-Maine), introduced S. 2022, the Ending the Diagnostic Odyssey Act, which would give states the option of providing federal matching funds for whole genome sequencing for Medicaid-eligible children with conditions that are suspected of having a genetic cause.
In California, state Assemblymember Brian Maienschein, whose district includes Rady Children’s, has introduced AB 114, the Rare Disease Sequencing for Critically Ill Infants Act, which would improve access to rapid whole genome sequencing for Medi-Cal beneficiaries.