She Has Her Mother's Laugh: The Powers, Perversions, and Potential of Heredity (49 page)

The next day, Tsoi's doctor visited her with forms to sign. “Then I realized it was something serious,” Tsoi said. Her doctor explained that Astrea did indeed have a severe form of long QT syndrome and had gone into cardiac arrest shortly after birth. It was hard for Tsoi to make sense of all the medical terminology, but she understood that surgeons were going to have to operate on Astrea's day-old heart to save her life.

After Tsoi and Li signed the forms, the surgeons implanted a cardioverter defibrillator in Astrea's heart. When her heartbeat lurched out of control, the defibrillator delivered an electric shock that reset her heart and established a normal rhythm again.

Astrea's medical team included a pediatric cardiologist named James Priest from Stanford Medicine's Center for Inherited Cardiovascular Disease. Priest sent some of Astrea's blood to a genetic testing company to see if they could find the cause of her long QT syndrome. Rather than look for a single mutation, Priest ordered a so-called panel test that could search for
mutations on a number of genes that are firmly tied to long QT syndrome. The panel's results might tell Priest which kind of tunnel was altered in Astrea's heart. Some tunnels pump sodium atoms, while others pump potassium. Different drugs for long QT syndrome work better on different tunnels.

But Priest was keenly aware of the limits of the panel test. For one thing, it was slow. He might have to wait a couple of months to finally get the results back—a vital window during which Astrea might benefit from being put on the right kind of drug. Priest also knew that about 30 percent of patients with long QT syndrome got no genetic diagnosis at all from panel tests. Scientists at the time were still a long way from identifying all the genes that can, when mutated, give rise to long QT syndrome. Thus, nearly a third of patients ended up in what doctors call
genetic purgatory.

In 2013, Priest and his colleagues were beginning to sequence the entire genomes of some of their patients to better understand their diseases. Rather than inspect one gene at a time, they wanted to look at all genes at once. When Priest talked about Astrea's case with his fellow scientists, they realized that genome sequencing might be both quicker and more thorough than the standard panel test. But they knew such an experiment would have no guarantees of success.

Priest spoke to Tsoi and Li, explaining what he wanted to do. “Everybody's genome is like a book with 23 chapters,” he told them. “You have two copies of each chapter, one from your dad and one from your mom. Whole genome sequencing looks for everything. It looks for missing chapters, missing paragraphs, every misspelled word.”

Tsoi and Li gave their consent, and Priest drew some blood from Astrea—now only three days old. He shipped it to Illumina, which rushed the job. Six days later, Priest got all their raw data. He set up a program to assemble the short reads into Astrea's entire genome, and then he searched through it for mutations that might be responsible for her long QT syndrome.

Astrea had millions of variants, of course, but Priest was quickly drawn to one in particular. She carried a rare mutation of one copy of gene called
SCN5A. That particular gene encodes sodium tunnels in the heart, and Priest himself had found that, in another patient, a mutation at precisely that same spot caused long QT syndrome. “It totally hit me over the head,” said Priest. “I wasn't going to find anything better.”

The next day, Priest informed Tsoi and Li of his discovery. Astrea, now only ten days old, was put on a drug to treat sodium channels. Priest then went back to Astrea's genome to wrap up the case, to confirm his diagnosis before writing up the results.

And that's when his story fell apart.

The Illumina technicians had sequenced Astrea's genome as they had mine and thousands of other people's. They broke open her white blood cells and chopped up the DNA inside. They then made many copies of those fragments—known as reads—and sequenced them all. Priest had used his computer to figure out where each read sat in Astrea's genome. Because the sequencer made so many reads, around forty of them lined up at every spot in her DNA. On average, half of the reads in a gene came from one copy of a gene, and the remaining ones came from the other. Priest found the SCN5A mutation in eight out of thirty-four reads. It wasn't a perfect fifty-fifty split, but it was close enough, Priest decided. He assumed that one copy of her SCN5A gene had the disease-causing mutation.

Priest followed up on the genome sequencing with a more focused exam of Astrea's DNA. He pulled out the SCN5A gene from some of Astrea's white blood cells and made millions of copies of it so he could examine it in fine detail. He expected to find a fifty-fifty split between the normal version and the mutant one. But he found no mutation at all. It was as if he had examined two different babies, one with a lethal mutation and one without it. “I was just flabbergasted,” he said.

Priest wondered if there was some unusual heredity in Astrea's family that had tricked him. Neither Tsoi nor Li showed any sign of having long QT syndrome. They never had any problems with their hearts, and Priest found that their EKGs were normal. It was possible that one of them carried an extra broken copy of SCN5A. Sometimes a mutation will trigger the accidental duplication of a gene but in a form that can't make a protein.
Perhaps Astrea had inherited a so-called pseudogene of SCN5A, and perhaps Priest had mistaken it for her working version. If that was the case, then SCN5A would have nothing to do with Astrea's ailing heart, and Priest would be back at square one. He'd have to start a new search for her long QT mutation.

To search for a pseudogene, Priest sequenced DNA from Tsoi and Li. Instead of sequencing their entire genomes, he sequenced only their protein-coding genes. Again, he ended up empty-handed. Neither of Astrea's parents had a pseudogene for SCN5A.

Finally, Priest considered the most extreme possibility: that Astrea was a mosaic. Perhaps the SCN5A mutation was only in some of her cells but not others. To investigate this possibility, Priest brought Astrea's blood to Stephen Quake. Quake, a Stanford scientist, had developed a way to sequence a genome from a single cell. Rather than throwing together DNA from millions of Astrea's cells, he could inspect them one at a time.

Quake and his team inspected thirty-six of Astrea's blood cells. In three of them, they discovered a mutation on one copy of the SCN5A gene. In the other thirty-three cells, both copies of the SCN5A gene were normal.

Quake's test confirmed that Astrea's blood was a mosaic. To get a broader survey of her mosaicism, Priest and his colleagues also examined cells from her saliva and urine. Now they had samples of cells that had developed from the three germ layers. (Blood comes from the mesoderm. The lining of the mouth comes from the ectoderm. And the urinary tract develops from the endoderm.)

In all three tissues, the scientists found the SCN5A mutation in between 7.9 and 14.8 percent of Astrea's cells. She was a mosaic through and through, in other words. And she must have become one before she had developed the three germ layers, when she had been just a ball of cells. One cell in that embryonic ball had mutated, and when it divided, it passed down that mutation to its descendants. The cells that inherited the errant SCN5A gene ended up mixing into all three germ layers.

As Priest and his colleagues were deciphering Astrea's mosaic nature, she recovered well enough from her surgery for Tsoi and Li to take her
home. The drugs Priest had recommended kept her long QT syndrome under control, and she enjoyed a happy infancy. One day, when Astrea was seven months old, Tsoi's phone rang.

“I got a call from the doctor, and she asked if Astrea was doing okay,” said Tsoi. Astrea was right in front of her, playing with toys, Tsoi said.

It turned out that Astrea's defibrillator had just shocked Astrea's heart. It had sent a wireless message to her doctors to let them know. They needed to get Astrea back into the hospital as quickly as possible. “I couldn't absorb that information fast enough,” said Tsoi.

When the Stanford doctors examined Astrea, they discovered that her heart had become dangerously enlarged—another risk posed by SCN5A mutations. Astrea would need a new heart in order to survive. Not long after Astrea came back to the hospital, her heart stopped, and her doctors struggled to bring her back, clamping a mechanical pump to her heart to keep it functioning.

“On the night that she was almost gone,” Tsoi said, “I was thinking, ‘If it's too hard or it hurts too bad on her, it's okay, just go.'”

Astrea recovered and regained her strength. And a few weeks later, a donated heart became available. Astrea underwent transplantation surgery, and she was back home again after a few days. The first few months at home were rough for the entire family, with Astrea throwing up constantly. But gradually she recovered. Except for having to take anti-rejection drugs three times a day, Astrea got her childhood back. She listened over and over again to songs from the movie
Frozen
. She did cartwheels with her sister.

For Priest, Astrea's heart transplant gave him a chance to find out once and for all if mosaicism had been to blame for her condition. After surgeons removed her heart from her body, they clipped off some pieces of muscle for Priest to study. On the right side of the heart, he and his colleagues found that 5.4 percent of the cells had mutant SCN5A genes. On the left, 11.8 percent did. Little grains of mutant cells were mixed in with the ordinary tissue. Priest and his colleagues built a computer simulation of Astrea's heart with those levels of mutant cells and let it beat. The simulated heart thumped irregularly, in much the same way Astrea's did.

Astrea had lost her mosaic heart, but the rest of her body remained a genetic mix. Yet now her SCN5A mutations could no longer threaten her life. Priest was left wondering how many other cases of long QT syndrome are actually the result of mosaicism like Astrea's. “It's hard to say I'll be involved in such an interesting case for the rest of my life,” Priest said.

The search for the causes of diseases has uncovered a number of cases of mosaicism. But scientists have also discovered some people in which
mosaicism can heal.

A team of Dutch dermatologists and geneticists described the first case of mosaic healing in 1997. They examined a twenty-eight-year-old woman whose skin was so fragile that even a gentle rubbing would raise blisters. This painful condition is caused by a mutation to a gene called COL17A1. Normally, skin cells use this gene to make a type of collagen that makes them stretchy.

Both of the woman's parents were carriers. They each carried a mutation on one copy of their COL17A1 gene. (They had different mutations in different locations—a detail that will turn out to matter tremendously in a little while.) Because each parent also had a normal copy of the COL17A1 gene, they could still make enough collagen to keep their own skin healthy.

The woman had the bad luck to inherit each parent's bad copy of the gene. Those defective copies were present when she was still a fertilized egg. They were passed down to every cell that zygote gave rise to. When she developed skin, her skin cells needed to switch on her COL17A1 gene to make collagen. The gene failed at its job, and she was left with skin that couldn't stretch.

Remarkably, however, the woman's doctors noticed that she had a few patches of normal skin on her arms and hands. They didn't blister when they were rubbed. The woman had been aware of some of the patches for as long as she could remember. Others had emerged more recently and were expanding. When the doctors looked at the molecular makeup of her healthy patches, they found healthy collagen.

Looking closely at the DNA in her cells, the geneticists figured out how
these patches had developed. Each arose from a single faulty skin cell. Before it divided, the cell duplicated its DNA. And during that duplication, it mutated in a peculiar way: It swapped a section of the COL17A1 gene between its chromosomes.

When the two daughter cells pulled away from each other, one cell no longer carried the woman's mutation from her mother. It had been replaced by the working portion of her father's COL17A1 gene. Now altered, the cell could make collagen again. And when it divided, its daughter cells inherited a working version of the gene as well. The woman's mosaics had repaired her defective genes.

Since that initial discovery, scientists have found more genetic diseases partially cured by mosaics. Their list now includes hereditary forms of other skin diseases, along with anemia, liver disorders, and muscular dystrophy. The growing inventory of mosaicism—causing diseases or healing them—raised the question of just how mosaic humans are in general. The definitive answer would come from breaking down people into their 37 trillion cells and sequencing every base of DNA in each one. For now, scientists are only carrying out rough surveys. But even these preliminary studies have come to one clear conclusion: We are all mosaics, and we have been so pretty much since our beginnings.

In the first few days of an embryo's existence,
over half of its cells end up with the wrong number of chromosomes, either by accidentally duplicating some or losing them. Many of these imbalanced cells either can't divide or do so slowly. From their initial abundance, they dwindle away while normal cells create their own lineages. If the supply of chromosomes is too abnormal—a condition called aneuploidy—then the mother's body will sense trouble and
reject the embryo altogether.

But a surprising number of embryos
can survive with some variety in their chromosomes.
Markus Grompe, a biologist at Oregon Health & Science University, and his colleagues looked at liver cells from children and adults without any liver disease, most of whom had died suddenly, by drowning, strokes, gunshot wounds, and the like. Between a quarter and a half of their liver cells were aneuploids, typically missing one copy of one chromosome.