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Sequencing Kids’ Exomes: More Good News

1000 genomeExome” hasn’t yet entered the normal lexicon, like genome has. Yesterday, for example, I wore my clinical exome T-shirt from Ambry Genetics to Zumba class, and a woman came up and peered at my chest.

“What the heck is that? What are all those letters? And what’s that little gap? A misprint?”

So I explained to the class what an exome is, and that no, my shirt had a small deletion, not a fabric defect.

Within 5 years, though, I think people will know what an exome is, because analyzing it will be as common as a CBC or blood lipid profile is today before visiting the doc. As costs decrease and gene discoveries increase, we’ve reached a tipping point, by definition when “a series of small changes or incidents becomes significant enough to cause a larger, more important change.”

Until “exome” becomes a household world, clever studies are illuminating pioneering applications of the technology.

The exome, the part of the genome that encodes protein, harbors 85% of disease-causing gene variants (we’re not supposed to say “mutation” anymore, but that’s what I mean). Results from several large studies have been published over the past 3 years, but a paper in last week’s Science Translational Medicine from Stephen Kingsmore’s group at Children’s Mercy–Kansas City offers the most promising results yet.

dna“It heralds the dawning of the new age of clinical genetics. We’ve been waiting for this to come around for 10 to 15 years, and it’s finally here,” says Robert Marion, MD, chief of the division of genetics at The Children’s Hospital at Montefiore and a  developmental pediatrician at the Albert Einstein College of Medicine, about the paper (he’s not part of the team). I devoured his book “Genetic-Rounds: A Doctor’s Encounters in the Field that Revolutionized-Medicine.”

Last month, the Journal of the American Medical Association published findings of two ongoing prospective exome sequencing studies of individuals with symptoms suggesting an inherited condition. A group from UCLA diagnosed 213 of 814 (26%) cases that hadn’t been diagnosed clinically or with single-gene tests or panels. The 26% rose to 31% if parents had their exomes sequenced too. The second report, from Baylor College of Medicine, diagnosed 504 of 2000 (25.2%) patients. Both studies weren’t just children.

I wrote in Medscape about the Baylor team’s interim results presented at the American Society of Human Genetics annual meeting in November 2012. At the same time I pitched the story to a top science magazine, whose editors had no idea what I was talking about. Now lots of magazines run kid exome stories. (I’ve a long history of being too-soon with biotech stories.)

By late 2012 the Baylor team had analyzed 300 exomes, with a 25% diagnosis rate. Most interesting to me, as always, were the cases. They reported several that illustrate two scenarios in which exome sequencing shines: a 2-year-old had Marfan syndrome but not the usual long limbs (“atypical presentation”), and a 9-year-old boy actually had two genetic diseases (“co-morbidities”).

Both boys were treated, once physicians knew what to treat. That also happened with the Children’s Mercy–Kansas City study that achieved a “molecular diagnosis” for 45% of their 100 families. They set up their study to extract a ton of information.

The more recent higher percentage – 45% compared to 25% — might be because the Children’s Mercy group considered only neurodevelopmental disorders (which include developmental delay, autism, and intellectual disability). By comparing newborns in intensive care units to older children who are veterans of multi-year “diagnostic odysseys,” the study revealed the great value of early exome sequencing. And they showed that the technology is cheaper and faster than a gene-by-gene approach.

Cifrão_symbol.svgCOSTS CONVERGE
When it comes to genetic testing, more is indeed better. Finally.

It’s been clear that exome and even genome sequencing would eventually cost less than single-gene tests ever since Myriad Genetics began charging $3,200+ for sequencing just the two BRCA genes. The new study homes in on the converging costs.

The investigation began at Children’s Mercy 3 years ago when the Center for Pediatric Genomic Medicine formed. “This is a retrospective look at the first 100 families enrolled in the genome center repository for diagnosis of neurodevelopmental disabilities,” Sarah Soden, MD, a developmental pediatrician and first author of the paper, told me. The 119 kids of those first 100 families had symptoms that didn’t exactly match those of any of the 2,400 or so known single-gene nervous system conditions.

Given my non-existent math skills I appreciate the cut-off at 100 families. Fifteen of the families had children hospitalized in the neonatal or pediatric ICU, and the rest were veterans of the average 7-year trek to diagnosis. The acutely-ill 15% had their genomes sequenced too, because exome sequencing can miss genes buried in GC-rich genome regions, which confound DNA replication enzymes like a stutter disrupts speech. Illumina provided instruments that can sequence genomes in under 50 hours, although analyzing the data takes a few days.


Considering the kids by the direness of their clinical situation proved telling. Genome sequencing diagnosed 11 of 15 (73%) of the families with kids in the ICU, while exome sequencing diagnosed 34 of 85 (40%) of the families with older children. The older kids were less likely to be diagnosed because their years of testing had ruled out many illnesses.

And that previous testing was expensive: on average $19,100 per nonacute family. The researchers estimate that sequencing would be cost-effective at up to $7,640 per family. Plus, there’s no metric for diagnosis of a child that takes days rather than years.

Of the 119 children, 18 had many symptoms because they had two genetic diseases. Five young patients had been receiving the wrong treatment, which was stopped, and 12 were treated correctly following accurate molecular diagnosis. So exome/genome sequencing isn’t only informational, it’s practical.

My favorite parts of exome and genome sequencing papers are the cases, as well as those I learn about when seeking comments for articles in Medscape. That happened when I talked recently with Dr. Marion, who says exome sequencing is already routine in clinical genetics.

“Our group had been following a family for 6 years, and they’d had every test that could be imagined. High-resolution chromosome testing, FISH, single gene mutation analysis for specific disorders — everything normal. The child had growth retardation, developmental delay, and multiple congenital anomalies,” he told me.

The parents, first cousins, knew that if the condition was inherited, they were carriers and every child would face a 1 in 4 risk. Dr. Marion sent a blood sample from the 6-year-old to have his exome sequenced just when the couple had become pregnant again.

“We found a mutation in a gene we’d considered (H syndrome), but the child didn’t fit completely. We then tested the fetus and unfortunately it was affected,” Dr. Marion continues. The parents ended the pregnancy because they felt they couldn’t care for two children with the condition, and appreciated the information. Only 50 cases of H syndrome have been reported.

Sequencing the exomes of parent-child trios, like in the syndrome H family, is especially informative because if the parents don’t have mutations that could cause the condition, then their child probably has a new and dominant mutation. And that means it’s unlikely to repeat in a sibling.

Dr. Soden describes a child in the Children’s Mercy trial who also “didn’t fit.” He had autism, up to 30 seizures a day, and by age 3 had a tremor and difficulty walking. By 10 he was wheelchair bound. A series of photos in the paper show his initially beautiful face becoming slightly skewed as he grew, a common finding in inherited conditions.

“This patient had gone years without diagnosis and enrolled for whole exome sequencing, with his parents. That identified a mutation in the PIGA gene that has historically been associated with a blood disease, but had very recently been associated with neurologic disability in infants. All patients described had passed away before a year of age, and this kid was 10 at the time,” Dr. Soden says. Pyridoxine (vitamin B6) has helped children with similar syndromes, so maybe it will help him.

The new study shows that exome sequencing can reverse the diagnostic trajectory, going from genotype to phenotype. Dr. Soden loves it. “What’s so exciting about genomic medicine is the practical side. Diagnosing the patient provides answers to families and physicians, and at the same time we can make discoveries.”

But Dr. Marion waxes wistful about handing over the excitement of the hunt to the precise new tool that is exome sequencing.

Dr. Marion with a young patient. (Children's Hospital at Montefiore)
Dr. Marion with a young patient. (Children’s Hospital at Montefiore)

“The bad part for me, being a cranky old clinical geneticist, is that it takes out of our hands the art of clinical genetics. In the old days we’d look at a child and analyze the information and come up with a differential diagnosis that might include 3 or 4 disorders. We’d go through the list, ruling out diagnoses. Now we recognize a kid has multiple congenital anomalies and send off samples for testing and get answers and try to fit the kid into the identified condition. But it’s definitely worth the benefit to families, siblings and patients.” Dr. Marion has solved many such mysteries in his career. In the photo he’s with a patient, now a teen, whose genetic disease (mucopolysaccharidosis type VI) he could name just by looking at her, followed up with genetic testing of course.

Although studies from Baylor, UCLA, Children’s Mercy, the NIH’s Undiagnosed Diseases Program, and others have certainly validated exome (and back-up genome) sequencing, it might be a few more years until the neighborhood nurse practitioner or urgent care physician pops a patient’s sample into a sequencer before venturing a diagnosis. “People trained more than 5 to 10 years ago have no idea how to use this information and will have to be retrained to do so,” says Dr. Marion. Medical schools are educating future physicians  in genomics.

Sarah Soden, MD (Children's Mercy-Kansas City)
Sarah Soden, MD (Children’s Mercy-Kansas City)

Dr. Soden expects to see exome sequencing enter subspecialty care first, and Children’s Mercy is helping with the education effort. “We have a genomic medicine master class where physicians spend a week with us and really learn what genome medicine is all about. Broad applications may be down the road, but in a center like ours we’re going to see it faster,“ she says. And Illumina holds regular workshops for health care providers to have their own genomes sequenced and interpreted, to learn the potential for diagnosing their patients.

Exome sequencing could be done on newborn heelstick blood samples.
Exome sequencing could be done on newborn heelstick blood samples.

Dr. Marion suggests another way that exome sequencing may nudge into the medical mainstream. “There’s going to be pressure on state labs to offer this in newborns. It will come from industry, because they will market directly to pregnant women: ‘Send blood from the newborn and we’ll predict the child’s health for the rest of his or her life.’ State labs will then say, ‘we have a 2-tiered system in which families that can pay get better screening’ and state health departments will say ‘we have to fix that.’ Babies will go home from the hospital and pediatricians will get readouts from the state lab of every polymorphism and mutation and predict what the person’s health will be like.”

It’ll be like cord blood storage.

But Kevin Davies, PhD, author of “The $1,000 Genome” and publisher of Chemical & Engineering News, tempers exome excitement.

“Even newborn genome screening becomes more and more plausible as the cost of sequencing continues to drop, we still await definitive evidence that this makes medical sense. I’m thrilled by the wondrous stories of diagnostic odysseys ending thanks to genome screening, but we need more than intermittent anecdotal reports to judge the clinical benefits. Trials are underway to address this key question. I also think the genetics community has a massive task ahead to communicate the benefits of genome screening to a general public that is still nervous, skeptical and even afraid of losing their genomic privacy.”


  1. Great article, thanks. Even more cutting edge than usual.

    Re: “…the genetics community has a massive task ahead to communicate the benefits of genome screening to a general public that is still nervous, skeptical and even afraid of losing their genomic privacy.”

    I’m a retired medical laboratory scientist but see this in the context of pharmacogenomic testing — even in medicare patients who I think desperately need to be tested to avoid complications from therapeutic drugs. Medicare pays for the testing, but people are afraid of what will be “on record.” Physicians are reluctant to add another level of concern to their practice standards, which are already too time-consuming. If they weren’t, I would consider coming out of retirement to promote testing.

    Alas, you mention “…disease-causing gene variants (we’re not supposed to say “mutation” anymore, but that’s what I mean).” The lexicon is part of the problem. Instead of using “mutation” as if I were biologically uninformed, I try to portray pharmacogenomics panels to friends and relatives in the context of links from metabolic networks to genetic networks. I’m not sure whether you think that is appropriate/ethical.

    I welcome suggestions from anyone willing to recommend a way to educate patients and physicians who have been taught to believe in theories that link beneficial “mutations” to the evolution of biodiversity and other mutations to disease. Until the lexicon incorporates what is currently known about cell type differentiation, some may be forced to use “mutation” as if they were biologically uninformed.

    Indeed, use of the term tends to sneak up on me, unless I look both ways before crossing the top-down bottom-up causation pathway — as I watch for oncoming traffic from physicists, chemists, and molecular biologists. Thanks for helping to keep that path clear.

  2. Thanks, James. I never try to be cutting edge — in fact, I try to stay away from what the rest of the media covers, looking for the unusual. The paper from Children’s Mercy was particularly well done with the stratifying of the patients.

    It was one of my sources, perhaps Dr. Marion, who made the comment about not being allowed to say mutation anymore. Variant is ok, it includes mutations, but I think we get subjective here. I love the example of homozygotes for the CCR5 mutation, protected from HIV.

    I think linking metabolic to genetic networks is just fine! It speaks to mechanism, and that is what is important in selecting treatments.

    Thanks for commenting!

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