The Digital DNA series explores the role of large-scale genetic testing in science, industry and society. We aim to understand both the benefits and risks of this emerging technology and see what the future may hold.

We talked to Dr. David Bick, Clinical Geneticist at the Smith Family Clinic for Genomic Medicine and Chief Medical Officer at the HudsonAlpha Institute for Biotechnology. He describes how the Smith Family Clinic utilises whole genome sequencing and research partnerships to diagnose patients with rare genetic diseases.

FLG: Can You Introduce the Smith Family Clinic for Genomic Medicine and The Work it Does?

DB: The Smith Family Clinic for Genomic Medicine started four years ago with the focus of looking for the cause of rare genetic disorders in patients who had gone here, there and everywhere to find a diagnosis for their condition.

We think the key to developing this medical office is we will employ whole genome sequencing when medically necessary, rather than just exome or panels. It turns out, unsurprisingly, that when you do whole genome sequencing you can find quite a number of diagnosis that other sequencing methods don’t find.

Whereas some of the testing that we do is covered by insurance, often the whole genome sequencing is not. We are very fortunate to have what is known as the “Hero Fund” in which qualified patients may receive full or partial funding for office visits and/or whole genome sequencing. The Hero Fund is made possible by philanthropic donors who want to help those who may need this clinical care or testing and might otherwise not be able to receive it. We also work very closely with the HudsonAlpha Clinical Services Laboratory that performs the whole genome sequencing testing and analysis. Like other geneticists around the world, we are sometimes surprised by what we find in the genome!

FLG: Why is Whole Genome Sequencing More Effective at Diagnosing Rare Diseases?

The alternatives to whole genome sequencing are usually panels or exome sequencing. The exome is the 1-2% of the DNA that contains the coding regions. Panels work by testing the patient’s DNA specifically for a range of pre-selected gene variants. However, a panel might not contain the gene variant that the patient has if the patient’s phenotype is quite rare. The doctor might either choose the wrong panel or the gene might be so newly discovered that it’s not yet on a panel.

As the price of whole genome sequencing has been coming down very rapidly in the last few years more and more groups are replacing exome sequencing with whole genome sequencing.

FLG: What are the Limitations in Using Whole Genome Sequencing to Make a Disease Diagnosis?

DB: We know that 30% of the time you’ll make a diagnosis in a rare disease situation using whole genome sequencing. However, we see a number of individuals who we believe have a rare genetic disorder, but the whole genome sequencing doesn’t identify it. Often this is because the error in the patient’s gene has yet to be connected with a human disease.

Of the 20,000 or so genes in humans maybe only 4000- 5000 have been connected to a human disease. We know what many of the 15,000 genes do; for instance, this gene makes a protein that works in the brain, this gene makes a protein that works in the kidney. But at this point for the 15,000 genes no one has connected a mistake in those genes with a particular medical condition.

So why is that important? Because there are so many new genetic conditions that have yet to be discovered – in other words a connection between a particular gene and a disease haven’t been made yet. If you’ve got the whole genome of an individual and you don’t find the answer straight away, then you can go back to that genome in year or 18 months and see if something new has appeared in the literature.

You can look back at your exome data but the capture array will likely not be up to date with new gene discoveries and you would most likely have to repeat the test.  Whereas with whole genome sequencing you obtain the whole genome and that sequence is valid from year to year to year.

FLG: What Services Do You Offer for Patients?

DB: Our office receives calls from either the patients and/or their physicians and we then try and make an initial assessment to identify if a patient will benefit from the clinical care we can offer.

As well as obtaining pertinent documentation from their physician, one of the most important on-boarding features we have is called our ‘Genome Gateway.’ Through the information gathering tool known as Genome Gateway we engage with our patients and families and have them provide us with additional information, because often families will know more about their medical history than one individual physician. Many patients might have seen a dozen different physicians around the country, so it’s very important for us to get this information prior to an appointment. 

We also use our Genome Gateway to provide educational information to patients and families. When a patient puts their information into the Genome Gateway we will also provide them with relevant learning modules – like what is a gene, and how does a gene cause disease? We also provide information on our location, an introduction to our staff, insurance and ethical issues. For example, if you have a genetic test there’s a US law that says it’s illegal for an employer or healthcare provider to discriminate against you based on your genetic test results. As patients come to us armed with a basic understanding of genomics and what the office can do for them, their questions become much more focused on the problem at hand.

When patients arrive, our administrative team greets them and completes any additional paperwork that may be needed prior to the appointment and familiarizes the patient and family with our office prior to the patient being seen. The clinical team will complete a physical exam and a family history. Based on that information we’ll say to them ‘here is some genetic testing that might make sense for you.’ We often find ourselves in a situation where we can offer them a simple genetic test that might give us the answer; and if it does that’s great.

But if it doesn’t, then we can drop back and use whole genome sequencing. Sometimes we can find answers once we’ve done whole genome sequencing, and that’s terrific. But in the incidences where we don’t, the Smith Family Clinic is also a research enrolment site, so patients can consent to share their information with the research community here at HudsonAlpha.

FLG: How Do You Work with the Research Groups at HudsonAlpha?

DB: There are research groups at HudsonAlpha that are very interested in the rare disease space. If we don’t find something from a clinical perspective then we can now, with the patient’s written consent, provide their medical information to a research group.

Because in the clinical laboratory you are bound by what is known. If you find a gene that looks curious and interesting but there is not a lot of existing research on it, then it’s not something you can put into a clinical report. But when we can’t find a clinical answer our research group can have another try. The research group can try and look for genes that we don’t know what they are yet – genes of uncertain significance.

There might then be the opportunity to discover either a new gene or a new phenotype connected to an old gene. Last week, we were analysing a genome and came across a change in a patient’s NRXN2 gene that hadn’t been previously connected with a patient condition. But when we went to our research group colleagues, they had seen a number of similar cases. We are now contacting people around to world to further research this gene.

FLG: How can Doctors use a Rare Disease Diagnosis to Inform Patient Treatment?

DB: If we find a diagnosis, there is hope that a treatment would be available. At present, most genetic diseases don’t have treatments, although for a few hundred genetic diseases there are specific therapies. For example, we know that for PKA we give patients a low phenylalanine diet. Diagnosis also helps physicians recommend other treatments that might aid patients, even if there is no specific one for their disorder.

For example, we had a woman who came to see us with recurring fevers, and we found she had a different variant in a gene called NLRP3. That information enabled her physician to order her a very specific medication that provided her a great deal of symptomatic relief. You will sometimes find things in genomes that can be a bit surprising!

FLG: Anything Else?

DB: There has been a number of people that have started to approach our medical office who don’t have a specific genetic condition but are interested in what their genome might tell them – so called elective genomics.

We have started to make our clinical care available to these individuals. With these patients, at least 2-3% of the time you’ll see genetic changes that can impact these patient’s long-term medical care that they had no idea about. So that’s another area that our office has become involved in.

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