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Genome study solves twins' mystery condition

June 15, 2011 By Erika ECH Check Hayden This article courtesy of Nature News.

Sequencing ends years of speculation over children's rare disorder.

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Two years ago, 13-year-old Alexis Beery developed a cough and a breathing problem so severe that her parents placed a baby monitor in her room just to make sure she would survive the night. Alexis would often cough so hard and so long that she would throw up, and had to take daily injections of adrenaline just to keep breathing. Yet doctors weren't sure what was wrong.

In a paper published today in Science Translational Medicine1, researchers led by Richard Gibbs, head of the Baylor College of Medicine Human Genome Sequencing Center in Houston, Texas, describe how they sequenced the genomes of Alexis and her twin brother, Noah, to diagnose the cause of her cough — a discovery that led to a treatment. Today, Alexis is playing soccer and running, and her breathing problem has gone, says Alexis's mother, Retta.

"We honestly didn't know if Alexis was going to make it through this," Retta Beery says. "Sequencing has brought her life back."

At age 5, the Beery twins had already been diagnosed with a genetic disorder called dopa-responsive dystonia, which causes abnormal movements, and had been taking a medication that was apparently successfully treating the condition. When Alexis developed a worsening cough and breathing problem, the twins' neurologists did not think it was related to her dystonia.

The twins' mother Retta Beery, whose husband Joe is the chief information officer at Life Technologies, a biotechnology systems and services company headquartered in Carlsbad, California, pushed for the childrens' genomes to be sequenced to find a definitive answer. The company helped fund the study at Baylor, which used Life's SOLiD sequencing technology to find that the twins carry mutations in a gene called SPR that encodes the enzyme sepiapterin reductase, which was previously linked to some cases of dopa-responsive dystonia.

Sepiapterin reductase enables the synthesis of the neurotransmitters dopamine and serotonin. The twins were already taking a dopamine precursor for their dystonia. So the study suggested that they might benefit from taking a chemical precursor of serotonin, 5-hydroxytryptophan, as well. A month after starting the treatment, Alexis's breathing problem had disappeared. Noah's handwriting has improved and he is also able to concentrate more in school, Retta Beery says.

Chalking up a win

The discovery is a win for genome sequencing in the clinic, which has already been used to guide cancer treatment2 and to diagnose and treat a handful of rare diseases whose origins are difficult to discern, and so hard to treat3.

"This study represents a good example of how genetic diagnosis of a rare genetic condition directly impacts treatment," says Joris Veltman of Radboud University Nijmegen Medical Center in the Netherlands.

Indeed, work like this is giving scientists hope that they will soon be able to 'solve' the genetic origins of almost all rare diseases and conditions. This is important because the rarer conditions by definition afflict fewer people than major killers such as heart disease, and so attract little funding for studies. Nor is it possible to organize large clinical trials into conditions that affect so few people (see 'Genomics focus shifts to rare diseases').

There are also relatively few medical doctors who are expert in diagnosing rare diseases, so these conditions are often undiagnosed or misdiagnosed, and available treatments go unused. This is something Retta Beery knows all too well. Her children were incorrectly diagnosed with cerebral palsy at the age of two, and did not receive their correct diagnosis — and first effective treatment — until the age of six, after being subjected to hundreds of tests. And Alexis endured six years of inconclusive tests before sequencing pinpointed the cause of her breathing problem, Retta Beery says.

The work published today suggests that sequencing could shorten diagnostic odysseys like these, because it tests for all possible genomic mutations at once, thereby guiding the way towards treatments aimed at particular biochemical pathways, and does not need to be ordered by specialists in rare diseases. Gibbs predicts that 90% of disorders caused by single gene defects will be solved in the next three to four years.

"The availability of unbiased whole genome or exome sequencing will make an enormous impact on our opportunity to diagnose and treat patients with rare disease," agrees Veltman, whose centre is now offering exome sequencing — sequencing just the coding regions of genes, rather than the whole genome — to patients with disorders including intellectual disability, blindness, deafness, movement disorders and hereditary forms of cancer.

The big question is when whole-genome sequencing will be inexpensive enough for routine clinical use. Gibbs estimates that the study released today cost about US$100,000, including $30,000 to sequence each twin's genome, and took two months. But some companies are offering sequences for as little as $5,000 to $7,500. Researchers think that when sequencing drops to $1,000 per patient, it will become more widespread.

Beery says that for other families who need it, that day cannot come soon enough.

"It's ridiculous to think of the amount of time and money that we and our insurance company have spent, and the amount of suffering our kids went through, when they could have had their blood drawn once and got the answer," Beery says.

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