by Mark Dunning
Well, it’s November and we are still summarizing the International Symposium on Usher Syndrome and Related Diseases that took place in May. That should be heartening for our readers. Obviously a lot happened at the conference.
A lot is happening in the real world, too, especially when it comes to diagnosing Usher syndrome and understanding the genetics. Now, if you or your family member have already been genetically tested and an Usher syndrome mutation has been identified, you might wonder why you care about the testing of others. I mean, besides the fact that you are a nice person.
I’ve said this a lot, but it always bears repeating: to find a cure is going to require the efforts of all Usher families. We need their natural histories, their genetic information, their experiences, and yes, their money (or at least the money they might help raise). Eventually we will also need Usher families to participate in clinical trials. In short, we want to find as many Usher syndrome families as possible.
That’s what makes the sessions on genetic screening so important. Like I wrote earlier, the good news is there is a lot going on.
A DNA based screening test for Usher syndrome
University of Iowa Carver School of Medicine and Boys Town National Hospital
Dr. Kimberling has been working on an inexpensive screening test for Usher syndrome. The test looks for the most common mutations in all known Usher genes. The idea is that this test would be part of a tiered approach. A screen essentially tests one chromosome. But remember, Usher syndrome is autosomal recessive, so both chromosomes need to have a mutation for it to actually be Usher syndrome. The second tier is DNA sequencing to verify the first tier finding.
One interesting result of their testing so far is that more than 10% of children with severe to profound sensorineural hearing loss may have Usher. That’s much higher than was historically believed to be the case.
Why you care
Genetic testing is expensive. I speak all the time with adults who have been diagnosed with Usher but have never had it confirmed genetically because their insurance wouldn’t cover it. A screen like this would make the most basic testing more widely available at a low cost. Remember, finding everyone with Usher is a good thing for everyone with Usher.
In proof reading this post, Jennifer made another good point for why you care. Her words: “To me the big ‘why you care’ point is the impact of adjusting the prevalence upward so dramatically. For years we have been saying that Usher syndrome is rare, citing the prevalence of 1 in 25,000 Americans derived from several older studies. Extrapolating from the new Kimberling data gives us something closer to 1 in 6000, which is more common than a lot of higher profile genetic diseases. This could potentially give us a lot more leverage in funneling research dollars to Usher studies as well as enhance our general efforts to raise awareness about Usher syndrome in the social, educational, and clinical realms."
An excellent point.
Developing more comprehensive genetic screening strategies for congenital sensorineural hearing loss (SNHL)
University of Iowa
All the states in the US and many other countries do a standard newborn hearing screen. As a result more than 4000 infants are diagnosed with severe to profound SNHL each year in the US. According to Dr. Smith, screening programs have focused on follow-up physiologic tests to determine how well a given child hears. Genetic testing has been used to confirm the diagnosis but Dr. Smith argued that we need to develop a more comprehensive strategy for using DNA testing as part of the screening process.
Why you care
This is a frustrating point for many of us. We already catch most kids with Usher through the newborn hearing screen (though Usher 3 kids may slip through with their progressive hearing loss). However, a lack of a strategy for including genetic screening as part of the newborn hearing protocol means a lot of these kids slip right through our fingers. We find them again later when they are late walkers or begin to have problems seeing at night. We shouldn’t lose them in the first place. Imagine pairing a low cost genetic screen with the newborn screen and you see where Drs. Smith and Kimberling are going with this.
Asper’s diagnostic tool for Usher syndrome
Institute of Human Genetics, University of Regensburg, Germany
The OtoChip sequencing array for hearing loss and Usher syndrome
Partners Healthcare Center for Personalized Genetic Medicine
I’m putting these three together because they are all genetic tests for Usher syndrome. What is kind of cool about the three is that they each are aimed toward a different diagnostic population. The Asper diagnostic tool is specific for Usher syndrome. So if a patient is suspected of having Usher, this test aims to confirm it. But say a patient has hearing loss or vision loss but it’s not clear if the cause is Usher or something else. That’s where the RetChip 1.0 and the OtoChip come in. RetChip 1.0 tests for a bunch of different genetic causes of RP including Usher syndrome. The OtoChip tests for a bunch of different genetic causes of hearing loss, including Usher.
Why you care
Having multiple paths that lead to an Usher diagnosis is critical. As we just saw in the talk by Dr. Smith, we catch a lot of kids with the newborn hearing screen. They presumably would be candidates for the OtoChip test since they wouldn’t necessarily be demonstrating any vision problems yet. We also know that a lot of kids slip through our fingers at that point and don’t show up again until they start to have vision problems. The OtoChip would still be a viable test but they would also be caught if the RP was the focus and the RetChip 1.0 was used. Again, the more families we identify the better and these give us several ways to do so.
The utility of databases in diagnosis
Laboratoire de Genetique Moleculaire, CHU Montpellier, Montpellier, France
We’ve talked about Dr. Kimberling’s DNA screen that tests for common mutations. Tests like the OtoChip and others like it seek to find a specific mutation no matter how unique. This has led to a number of different variants being identified. Dr. Roux and her colleagues have created a database to store those mutations that is searchable for all researchers. These can then be folded in to the screens and the OtoChip-like tests so that they are more comprehensive and find more patients faster.
Why you care
Read that last line again. A database of all known mutations helps us to more quickly identify more people. That’s a good thing.
Lessons from the UK National Collaborative Usher study
UCL Institute of Child Health, London, UK
One of the things we have long struggled with is connecting genotype (the genetic mutation) to phenotype (the physical changes caused by that mutation) in Usher syndrome. This study is an attempt to do that. They studied 190 families in the UK with Usher syndrome. They were able to identify 80% of them by sequencing known Usher genes. They also identified a number of new mutations in the process.
Why you care
This is exciting stuff. There have been very few comprehensive phenotype/genotype studies done on Usher syndrome. Being able to predict phenotype by genotype would be a great thing for all Usher patients. The question I hear most often is “what does the future hold for me or my family member?” This type of study can help us to be able to find the answers. It will be interesting to see the results. And remember the database talked about by Dr. Roux. This study identified 80% of the patients using known genes. That means 20% were unique. It takes a lot of work to identify those novel mutations. But if all newly discovered Usher mutations were put into a database that researchers around the world could easily reference, the next time a similar study is done those new mutations can be included.
OK, next post on the symposium should be the last. We should be finished just in time for the next symposium!