Thursday, February 23, 2017

Rare Disease Day 2017

Diagnosing diseases is a tricky business requiring a formidable breadth and depth of knowledge and the skill to apply that knowledge. Patient diagnosis becomes even more difficult for rare diseases: quality reference data may not exist and a physician might only see one such patient in her entire career. According to the National Institutes of Health, there are between 6,000 and 7,000 rare diseases affecting from 25 to 30 million Americans, making it likely that most, if not all, health care professionals have seen these patients in their practice but may not have known it. Oftentimes, a patient with a rare disease gets misdiagnosed as having a more common disease with a similar set of symptoms. In such cases, the misdiagnosis can lead to ineffective, or even harmful treatment; this is a danger even for patients who have rarer forms of a common disease.

Next Tuesday is Rare Disease Day, a day devoted to raising awareness of rare diseases, learning from the patients and families living with these diseases, and promoting the research that is being done to find treatments.

What is a rare disease?
A disease is considered rare if it affects fewer than 1 in 200,000 people in the US, or fewer than 1 in 2,000 people in Europe. The more than 6,000 known rare diseases range from several kinds of cancer, to neurological, skin disorders, and diseases affecting the lungs. According to the Orphanet, a portal for rare diseases, most of these have no cure. Of the known rare diseases, about 80% have an established genetic cause, while the remaining 20% are thought to be caused by environmental factors, like infections. Approximately half of the people with a rare disease are children.

What is Rare Disease Day?
Rare Disease Day began in 2008 in Europe by EURORDIS and the Council of National Alliances as a day to raise awareness about rare diseases and the people living with them. The day also raises awareness for policy makers and health professionals. It occurs on the last day of February, which is Tuesday the 28th this year. Rare Disease Day has grown since its inception: last year there were events in 84 countries.

What are some important issues affecting people with rare diseases?
One of the largest problems facing patients living with rare diseases is a delay in diagnosis. From the time a patient with a rare disease first sees a doctor to the time of correct diagnosis averages 4.8 years, but can take up to 20 years. During this time, on average, the patient will see more than 7 physicians. There are several reasons why this diagnosis can take so long.
  • Rare diseases are, by definition, rare, meaning that a particular doctor may have never seen a similar patient before. In this situation, the patient might leave the doctor without a diagnosis, or be sent to another physician’s office to aid in the diagnosis.
  • To further complicate diagnosis, many rare diseases have symptoms that are similar to those associated with a more common disease, so misdiagnosis is very common among these patients.
  • Also, symptoms of the same rare disease can present themselves in different ways in different patients, leading to confusion. These misdiagnosis can be costly, potentially harmful, and frustrating for the patients and their families.
  • Sometimes a physician will correctly identify the rare disease, only to inform the patient that there is no cure for the disease, or there is an incomplete treatment.
Rare diseases pose a public health problem: each rare disease may be uncommon, but rare diseases combined affect a large population of patients, their families, and their caregivers.

This year is the 10th Rare Disease Day and has a special theme of research. The slogan, with research, possibilities are limitless, focuses on the important role that research plays in diagnosing and treating rare diseases. Researchers studying rare diseases can increase knowledge of how a particular disease occurs, which parts of the body are affected, or how the disease could be treated. This information could directly impact a patient’s life by improving diagnosis rate and increasing treatment options. Further, researching rare diseases can also provide insights into more common diseases. The Rare Disease Day press release highlights this point by saying: “Research is key. It brings hope to the millions of people living with a rare disease across the world and their families.”

Rare Disease Day shines a light on the need for international collaboration between researchers and clinicians. Since there are so few patients with a particular rare disease, increasing communication around the world can link these isolated patients together, building a support system and increasing knowledge about their shared disease. “Rare Disease Day 2017 is therefore an opportunity to call upon researchers, universities, students, companies, policy makers and clinicians to do more research and to make them aware of the importance of research for the rare disease community.” - Rare Disease Day press release

I recommend watching the 2017 Rare Disease Day video ( and learning more about individuals living with rare diseases by reading their stories here:

Monarch Initiative members recently attended the IRDiRC – International Rare Diseases Research Consortium (pictured below), and you can read more about this important conference here.

Sources and more information:

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Tuesday, February 21, 2017

What's in a (gene) name? That which we call a gene by any other name would confuse a researcher

If you had told me that I would spend my PhD years studying a gene called Falafel, I probably would not have believed you. Yet, that is exactly what happened to me (I was also briefly studying a gene called Bazooka). When working with fruit flies, researchers often come up with entertaining names for newly discovered genes; however, these same genes in mammals can be quite different. For instance, Falafel is called PP4r3 in humans. This discrepancy in gene names (also called gene symbols) can be confusing, and part of the Monarch mission is to ease cross-talk between interspecies genotype data.  As a researcher, it can be hard to remember what a gene is called in different species, and this problem becomes more difficult if a gene name is changed. Thankfully, gene names are infrequently changed, and there are groups committed to ensuring that gene names are systematic and regulated. Recently, however, I was prompted to think of alternative names for MARCH7, a gene discovered by Monarch Principle Investigator, Melissa Haendel, in the 1990s.

Why does the name of a gene change? There are several reasons why a gene name might be changed or updated, for instance: if a newly discovered gene has no known function, but later is known to be a part of a family of genes, that newly discovered gene could be renamed to match the family it now belongs to. This is the case of the gene MARCH7, discovered by Haendel during her PhD work. Haendel originally named the gene Axotrophin, but later Axotrophin was discovered to be a member of the MARCH (membrane associated ring-CH-type finger) family of genes, and was renamed. However, MARCH7 is about to be renamed - yet again. The HUGO Gene Nomenclature Committee has recently determined that MARCH7, along with several other genes, will be renamed because, when used within Microsoft Excel (a tool popular among researchers), the gene symbol MARCH7 gets corrupted.

The Excel corruption issue occurs when a gene symbol is recognized as a date, and the original text string is irrevocably overwritten. For example, in the MARCH family of genes, MARCH7 is converted to 42801 which is then visually rendered as 7-March. Because 42801 is not recognized by computers and other software as even being a gene name anymore, it leads to incorrect analyses later. This formatting error befalls other genes families as well: SEP, SEPT, APR, MAR, DEC, NOV, and OCT. While HUGO recognizes that this is not a traditional reason to change the name of a gene, the change has been deemed necessary.

There is another formatting issue in Excel that affects a subset of genes, those named with RIKEN identifiers. These identifiers are in the form “nnnnnnnenn” where n is a digit, for example, 3400000e12. RIKEN identifiers such as these are converted into floating numbers, for instance 3400000e12 would get converted into 3.4e+12. These conversions are irreversible; once changed, the user can no longer get the original gene name back.

Blaming Excel for these errors might be the easy thing to do, but researchers have the responsibility to ensure that their data is accurate. There are several workarounds that researchers can take advantage of to limit these identifier errors. In 2004, Zeeberg and colleagues published steps to stop the automatic reformatting of gene names and also shared a programming script that can detect if a gene name has accidentally been converted into a date or into a floating number format. But it seems that researchers are not taking advantage of these resources. A recent article by Ziemann et al. examined lists of gene names from 18 journals published in the last 10 years and found that almost 20% of papers with gene lists had erroneous gene names in those lists. Ultimately, HUGO has decided that the best solution for this gene symbol debacle is to change the names of these problematic genes.

So now the researchers that are most familiar with the MARCH family of genes have been tasked with renaming these gene symbols. What should be the new symbol for MARCH7? One suggested idea is MAUL; our own Melissa Haendel supports this name because, as she said, “Axotrophin killed everything I put it in!” While the semantic future of MARCH7 is yet to be determined, we do know that these gene symbol name changes will have far-reaching effects. In my blog post next week, I will discuss some of these ramifications and delve deeper into the problems that are caused by divergent gene symbols.