Editor’s Note:

At the Future of Genomic Medicine VII conference in March 2014, leading experts in genomic research and clinical application discussed the expanding influence of genomics on the practice of medicine. Medscape asked Arthur L. Beaudet, MD, Professor in the Department of Molecular and Human Genetics at Baylor College of Medicine in Houston, Texas, to offer insight on how advances in genetics are changing the way we approach rare diseases.

Medscape: How have newer genetic testing strategies changed the diagnosis of rare diseases?

Dr. Beaudet: I have been involved in diagnosing and evaluating children with rare disorders for more than 40 years now. When we first started out, there was very little ability to make specific diagnoses. We had descriptive diagnoses and there were some syndrome names, but we didn’t know exactly what was going on. And there were these endless arguments about “lumpers” and “splitters” and whether or not certain patients belonged in the same group.

A big change happened with newborn screening. We went from testing only for phenylketonuria (PKU) to testing now for dozens of rare disorders that are diagnosed at birth and for which there is usually important management. That is now part of the newborn screening philosophy.

But still, for the majority of our patients who would come in with one or another disability, we did not usually have the ability to know exactly what their underlying problem was.

Today, with copy number analysis and sequencing analysis of the genome, we can get to a very specific understanding of what is going on in about 50% of the patients that we see with rare disorders. This has been a dramatic increase. We went from maybe 10% a decade ago to now 50%. I think it is going to continue to change rapidly so that, in the great majority of our patients with rare disorders, we will be able to know precisely which gene or genes are involved.

Medscape: What role can clinicians play in helping to establish a rare disease diagnosis?

Dr. Beaudet: A very careful description of what is going on with the patient is critical. Typically with rare disorders, once you know the diagnosis, the patients fit a fairly narrow pattern and they have very similar findings. You may see at family support groups, or if you go to meetings, that it is remarkable how many of the affected individuals are so similar to other affected individuals. But often they have almost bizarre findings, so the physician has to be a really good observer and document what is going on.

We do see a lot of wrong diagnoses, where someone says the patient has ataxia, but in fact they have a neuropathy. The more the physician can stick to describing specifically what the patient is doing or reporting and not try to label it as a particular diagnosis, the better. We have, for instance, lots of patients who initially get diagnosed with cerebral palsy and later get identified with any of 20 or 30 or 40 different genetic disorders.

Medscape: How can primary care clinicians best collaborate with patients and experts in diagnosing and managing rare diseases?

Dr. Beaudet: We run into a lot of people who I wouldn’t call average patients but highly educated people who have rare disorders. They typically get to know far more about their disorder than their physician, particularly their primary physician. The physician has to have the right philosophy in working with this individual who is going to be subject to all kinds of other common disorders — for example, they may get hypertension in addition to the neurologic disorder. The very educated patients are going to know a lot. They frequently have been to national scientific meetings about their disorder.

Then there is another class of patients who aren’t nearly as educated, are not inclined to go on the internet, and are not inclined to go to scientific meetings about their disorder.

I think it is frequently the case that patients– and it is often parents of children with rare disorders– know much more about their disorder than their physicians do.

For a physician to spend 10 hours studying up about a rare disorder would be a lot, but the parents may think nothing of spending 100 hours.

Maybe it is best to say that we should respect what the parents know and to go to the experts. Experts nowadays are not just in your state; they are anywhere in the world. You can deal with any expert anywhere in the world about a particular rare condition, and you can talk to that expert more easily than the parents can talk to that expert. You can send the expert an email and ask a question: “I am seeing this or that; do you think it is part of their disorder?”

Generally, there are only 100, 200, or 300 patients in the world [with each rare disorder], and the experts have devoted their life to research on this area, so they are quite happy to answer these kinds of questions. That would be another thing physicians could do — be comfortable about sending an email to the world’s expert no matter where they are.

Medscape: Where is research in this field headed?

Dr. Beaudet: We are going to see more and more diagnoses around reproduction. We are going to see more and more parents getting detailed genetic analysis, maybe a partial or complete sequencing of their genome, prior to conception, as they begin to plan for reproduction. And in the event that they have a risk for rare disorders, they can undergo a procedure called preimplantation genetic diagnosis, whereby they would have in vitro fertilization, and if there was a 1-in-4 risk for some rare disorder, they could choose that only the unaffected embryos would be implanted, so they would not actually have any living children with the rare disorder. That would be one direction.

Another group of rare disorders occurs by virtue of new mutations– that is, there is no carrier status in the parents. The parents have a perfectly normal genetic makeup, but these disorders can be diagnosed by direct prenatal observation. We are seeing big changes in what is now called noninvasive prenatal diagnosis, whereby one takes a blood sample from the mother. It seems quite likely that we will be able to actually sequence the genome of the fetus with a blood sample from the mother.

At this point, then, we would be making the vast majority of diagnoses of rare disorders either prior to conception– where we would not implant affected embryos– or we would make the diagnosis in the first trimester of pregnancy. That is going to be a dramatic difference.

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