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3340435836_d347c3ce3d_z-2Rachel knew there was something wrong. She knew it in her bones that ached continuously. She knew it in her gut, which persisted in rejecting most foods. She knew it in her joints, when she had to take a break half way through a tai chi session. And she definitely knew there was something wrong because at 28, she still had not had a period. She had lost count of the number of tests that had been done by the multitude of doctors over the years. You probably have a genetic disorder they said. It may be related to Kallmann syndrome, but you lack key symptoms so it is not that. There is no cure they said, and instead gave her birth control pills and told her to wait it out. But when an endocrinologist at the University of California, San Francisco, said she had the bone density of an 80 year-old woman and was essentially going through menopause before puberty, she got really scared. The endocrinologist suggested she get genetic testing to isolate the genes that may indicate Kallmann syndrome or some other rare disease. With genetic testing, Rachel may finally be getting the answers she has been looking for these fifteen uncomfortable years.

Rare diseases, like Kallmann syndrome, are sometimes called ‘orphan’ diseases because they are often neglected when researchers don’t feel the need to focus on them, drug companies don’t make enough profit in developing drugs for small groups of people, and research funding goes to the more popular diseases. However, according to the Global Genes Project, people with these rare diseases collectively amount to more than those affected by AIDS and cancer combined. Unfortunately, the lack of attention given to orphan diseases means that it can take on average seven years and sometimes a lifetime for a diagnosis to be made, as patients are passed from doctor to doctor, undergoing any number of inconclusive tests and progressively getting worse.

With the increasing availability and dropping price of whole exome sequencing, people with orphan diseases, which are 80% genetic in origin, may finally be getting the diagnosis they have longed for. Recent studies published in the Journal of the American Medical Association, revealed that exome sequencing leads to a diagnosis in 25% of cases. The exome is the 1% of the genome that contains genes responsible for making proteins. Eighty-five percent of disease-causing mutations are in the exome, so there is a relatively high chance that whole exome sequencing will find the disease-causing mutation.

In the United States, the Rare Diseases Act of 2002 defines a rare disease as “any disease or condition that affects less than 200,000 people.” 30 million people in the U.S. are living with rare diseases, which equates to 1 in 10 people. Fifty percent of these are children, making rare diseases the number one cause of death in children. The worst part is that the understanding of many of these diseases is so poor that it can be a challenge to get an accurate diagnosis, let alone an appropriate treatment.

According to a recent rare disease impact report by Shire, a company dedicated to developing treatments for rare diseases, people go an average of seven years before getting an accurate diagnosis. During this time, a patient typically visits eight different doctors, four primary care doctors and four specialists, and may get two to three misdiagnoses. In Rachel’s case it has taken longer. “I think I have seen ten medical doctors,” she said, “The first one said it’s just delayed development, don’t worry about it. Years later she was like oops, I have no clue.” Later specialists concluded she had a genetic disorder related to Kallmann Syndrome. However, they ruled out Kallmann Syndrome because she lacked key diagnostic symptoms like a lack of smell. “They performed all kinds of tests to try and figure it out. It was exhausting. I ended up just feeling depressed and weepy,” Rachel said.

Physicians face many difficulties in trying to diagnose a rare disease. It is difficult for them to be familiar with the symptoms and presentation of the 7000 rare diseases in addition to those of common conditions. Symptoms seen in many rare diseases are also seen in a variety of other conditions, including many common conditions. Physicians are trained to think of the more common conditions instead of the unusual conditions that might not necessarily be on their radar screen. This sometimes leads to misdiagnoses.

Rare diseases often present a wide variation in symptoms. A physician may be familiar with the classic presentation, but if they are seeing a patient that doesn’t fit perfectly into what they’re expecting to see, like in Rachel’s case, there may be a delay in getting to the right diagnosis. In such cases the patient may be sent to a specialist, but it can sometimes take a long time for patients to even get an appointment. If it is a condition where there are multiple body systems involved, the patient ends up going from specialist to specialist, before somebody puts all the pieces together and makes an accurate diagnosis.

Some rare disease advocacy groups, like the non-profit, In Need of a Diagnosis, are advocating for a medical specialty in diagnosis. They believe that someone is needed to take all the reports from the specialist and piece together these more complex medical puzzles.

Marsha Lanes, genetic counselor and spokesperson for the National Organization for Rare Diseases says, “I think, in a way geneticists are already playing that role to some degree, and I think that’s probably going to be even more the case, as sequencing becomes more part of standard of care…I think that there will be even more of a role for geneticists in that sort of all-encompassing multispecialty coordination role.” Increasingly patients with rare diseases are finding the answers when the finally are referred to geneticists and genetic counselors for genome sequencing.

Ten years ago, when the first doctor told Rachel that she had a genetic disorder related to Kallmann syndrome, there really was no way to make a definitive diagnosis. The Human Genome project had recently been completed and the first copy of the human genome published. Doctors and geneticists knew that this would have a huge impact on medicine and the way they prevent, diagnose, manage and treat disease. Unfortunately, at the time, sequencing a single genome came at the steep price of $100 million. Though slowly coming down, the price of sequencing the genome has been the major barrier in integrating it into clinical healthcare. By 2011, 10 years after the original genome was sequenced, the price had dropped to $10,000, due to the introduction of next generation sequencing, a technology that dramatically improved the rate and number of genomes that could be sequenced. Finally in January of this year, Illumina, a company that develops genetic technologies, announced the $1000 genome.

Erica Ramos, genetic counselor with the National Society of Genetic Counselors and Clinical Genomics Specialist at Illumina, explained that unfortunately this does not mean that you can go and ask your doctor for a $1000 genome sequence. “At Illumina, we were suddenly getting all kinds of questions about how to get the $1000 genome. This is where the communication of scientific information can be challenging to the general population. When we say, well yes, you can do $1000 genome, but it is in the context of a research study, and you have to be running these machines at full power and that means 18,000 genomes a year, and that’s just the data. There’s no interpretation with that, and that’s not in the clinical setting, which you need to be in to get results for medical care. Those are the things that don’t quite get out there.”

Ramos emphasizes that he infrastructure still needs to be built to make whole genome testing available for everyone at a reasonable price. The $1000 price-tag right now only refers to the money it takes to sequence a genome on a $10 million dollar machine that is only available in a few laboratories around the country. The increasing availability of technology, and the ability to easily interpret results in a clinical setting, are what will drive the price down.

“There are so many people out there who have been waiting for years and years to get answers. So many families who’ve been waiting to figure out what’s been going on with their kids, and traditional testing just hasn’t been able to get them that,” Ramos says, “But it ($1000 genome) will continue to drive the technology lower. The more information we have and the more genomes we have to work with, the more interpretation and analysis, which right now is the expensive part, will get cheaper too.”

For the time being, whole genome sequencing is only available in a research setting.

Clinically, however, whole exome sequencing is available for the still hefty price-tag of $10,000. When ordered by a doctor who has considered the symptoms and family history of a patient, this test is covered by some health insurance plans. As more genomes are sequenced and the genetic mutations for rare diseases are identified, there will be more information available for diagnosis and treatment.

There has been an increase in research in rare diseases and treatments for them since the passing of the Orphan Drug Act in 1983, which provided incentives and a structure for research of orphan drugs. Currently, however, there are fewer than 400 treatments approved by the Federal drug Administration for the over 7000 rare diseases. 95% of rare diseases don’t have a single approved treatment, according to Kakkis Every Life Foundation.

“A lot of patients and families tell us that it’s very important to them to understand the underlying reason for their health problems, even if treatment is not available. Just from a personal perspective, I think many patients are savvy to the to understanding that if the underlying genetic explanation has been identified there may be a higher chance then to develop some sort of therapy targeting that problem,” Lanes says.

Whole exome sequencing is what Rachel is counting on to get the answers she has been so desperately looking for. “When I started this journey, nothing like this was even available. It felt like a guessing game, being passed from doctor to doctor and treatment to treatment. I couldn’t have imagined that I would be here today, still not knowing for sure, and doing another test.” Rachel is trying to wait patiently the four months it will take to get her exome sequencing results. “I am hoping that this will be the test to end all tests,” she says, “I just want to know.”