Stanford's "molecular autopsies" hope to help grieving families

When Richie Quake, a vibrant 19-year-old engineering student, wasfound dead in his bed, his family was devastated. But when aconventional autopsy of the apparently healthy young man offered noanswers, his parents were gripped by another medical concern: Coulda silent but deadly condition be hiding in other members of thefamily?

Today, scientists at the Stanford School of Medicine are on aquest to find out, searching samples of Richie's tissue for geneticclues that might explain why the young man's heart suddenly stopped.

The "molecular autopsy" is believed the first time that whole-genome sequencing has been used to seek a cause of death, althoughthe Stanford team has used more focused genetic scans to investigate17 other sudden unexplained deaths.

Dr. Euan Ashley and his medical research team are scanningRichie's DNA for errors that might cause irregular beating of theheart, invisible during traditional dissection.

"We're applying new technologies to an age-old practice, tryingto work out why someone died, after they died," said Ashley, whodirects Stanford's Center for Inherited Cardiovascular Disease.Nearly half of healthy young people have normal findings at autopsy,so their deaths remain a mystery.

"Because so many of these conditions can be familial, it becomesmore important for surviving relatives," he said. "This has theopportunity to save lives."

The team's data is still under analysis, and their conclusionswon't be published until later this year. But they say they arezeroing in on a set of suspect gene mutations linked to oneparticular type of rare and poorly understood cause of suddencardiac death, caused by faulty electrical signaling in a beatingheart.

If confirmed, the genomes of surviving family members could besearched for similar flaws, and their health monitored closely.

Deadly heart flutters

Richie Quake seemed to be in perfect health. It was a morningthree years ago when the black belt in karate, with D.A.R.E. drugprevention posters on his wall, lingered in bed because he felt alittle chilly. Later that day, the Drexel University student wasscheduled to work at a nearby theme park, dressed in a Big Birdcostume.

"I kissed him good night the night before when he gave me a shirtfor my birthday," his father, Richard, told Stanford Medicinemagazine. "My wife talked to him that morning. ... She said, 'OK, Ilove you,' and she kissed him goodbye."

Following an autopsy, the coroner blamed a fluttering heart, orarrhythmia. But that's a symptom, not a cause.

"He was a very bright teenager, very active, a good kid," recallsStanford bioengineering professor Stephen Quake, a cousin ofRichie's father. "It's been a very difficult experience foreveryone, especially his immediate family, when there is noexplanation, no closure.

"We wondered: Is there something we missed? For his sisters, andmy kids, I wondered: What can we do for them to make sure we'retaking the best care of them?"

Anguished by the unexplained death, Richie's father insisted thecoroner collect both blood and tissue samples. "I told him, 'I needyou to save everything you possibly can for future testing,' "Richard Quake, a sales manager for an Internet auto auction site,told Stanford Medicine. "At the time, I really had no idea why Isaid that."

Encouraged by cousin Stephen, who last year had his own genomesequenced for under $50,000 and published in the journal Lancet,Richard Quake sent tissue samples to Stanford.

Such cardiac death is generally linked to a problem in thepumping heart. The heart operates on electrical impulses thatrhythmically stimulate the vessels, so blood can be pumped to thebody. These electrical impulses are controlled by pores called "ionchannels." Death can occur when the proteins for these ion channelsdo not function properly.

Scanning nucleotides

Stanford is not the only research facility searching, post-mortem, for killer genes. In Canada, a molecular autopsy of a 21-year-old college student found a genetic mutation that causes aheart problem called Long QT Syndrome. When tested, her mother wasfound to have the same mutation.

At the Mayo Clinic in Minnesota, Dr. Michael Ackerman hasperformed molecular autopsies of 49 young people who died suddenly.In seven cases, he found suspect mutations in a gene called RyR2,which regulates the influx of calcium into heart cells.

Such defects are dubbed "the perfect assassin" by Ackerman,because they leave no trace.

After Richie's death, his father sent his tissue to otheruniversity labs to see whether they could find known mutations. Buttests came back negative.

So the Stanford team has expanded the search, using powerfulcomputers to scan all 6 billion nucleotide letters in Richie'sgenome, focusing on regions that regulate proteins in the heartmuscle. Since there's no formal list, it's a big undertaking. Tomake matters worse, such defects are rare; a mutation could even beunique to a single family.

So far they have identified 200 genetic variants in the youngman's genome, many never before associated with disease. Which onewas lethal? That's what the Stanford scientists hope to learn.

"It's a situation where we're as blind as we can be -- the suddendeath of a healthy 19-year-old," Dr. Ashley said. "We have no otherhelpful side information."

Contact Lisa M. Krieger at 408-920-5565.ANALYZING THE DATA

FINDINGS TO be published next year: The team is zeroing in on aset of suspect gene mutations linked to one particular type of rareand poorly understood cause of

sudden cardiac death, caused by faulty

electrical signaling in a beating heart.

WHAT IT COULD MEAN: If a link is found, surviving family memberscould be searched for the same mutation, and their health monitoredmore closely.