Many common diseases are easy to diagnose and treat, thanks to scientific advances. But for those with rare conditions, finding answers can sometimes feel impossible. Dr. Susan Hiatt and her colleagues at the HudsonAlpha Institute for Biotechnology are dedicated to changing that by making diagnosis easier and faster for rare disease patients.
Susan is a Research Faculty Investigator in HudsonAlpha Faculty Investigator Dr. Greg Cooper’s lab. The Cooper lab sequences the genomes of children and adults with suspected rare genetic diseases and developmental disorders to try to find an answer for their symptoms. The research team is constantly learning and developing new sequencing and analysis methods to find the most genetic variation possible and provide the most diagnoses possible.
I sat down with Susan in the Mark C. Smith Library at HudsonAlpha to discuss her career journey, new role, and future plans for rare disease diagnosis.
Sarah Sharman: How did you become interested in the field of genetics?
Susan Hiatt: In graduate school, I did research on C. elegans, which is this fun little worm that’s used as a model organism. I wasn’t in the genetics department and didn’t necessarily study genetics, but everything I did was based on genetics. I used genetics a lot to answer questions in my worm model.
From there, I went to RefSeq, which is an NCBI database that houses reference sequences. They define a lot of reference sequences for the research community. I learned a lot about genomes and genome annotations in doing that job. I really enjoyed my time there, but I realized I missed research. I wanted to be publishing papers and asking new questions all the time.
As I started looking for research positions, I found Greg’s lab. Their work really matched my experiences of trying to understand the genome, how it works, and how changes in the genome impact health and disease. With my move to Greg’s lab, I made the jump into human genetics, which has been really cool to see the application of everything I picked up along my educational and career journey.
Sarah: What is the most exciting part of your job today?
Susan: Every case presents a unique puzzle. With long-read sequencing especially, we encounter previously unseen structural variants that demand close examination and collaborative analysis. Since many of these variants are entirely novel, there’s no definitive answer waiting to be found. Instead, I draw on all available data to unravel the mystery. This investigative aspect is particularly rewarding for someone like myself who loves puzzles and thrives on challenges.
Sarah: How is your research contributing to helping our society?
Susan: Diagnosing a previously undiagnosed condition has a profound impact on individuals. It alleviates years of uncertainty, empowers patients to connect with communities facing similar challenges, and validates their struggles. Beyond the individual, our work contributes to a broader knowledge base. We submit all of our variants to ClinVar and other databases, which contributes to the collective understanding of genetic mutations. This published data informs diagnoses for future patients encountering the same variant, potentially impacting entire communities. Ultimately, this collaborative effort paves the way for functional studies, which could lead to the development of future treatments.
Sarah: Can you share an example of a case that really solidified that this was the right career path for you?
Susan: When we first started sequencing individuals with rare diseases, the most popular and affordable technology was exome and short-read genome sequencing. Some patients found answers with these technologies, but not many. As technology advanced and knowledge in the field grew, we began hearing about groups that were reanalyzing patient genomes. So, we decided to look at some of our older cases. The very first case I reanalyzed went from no reportable results to a pathogenic variant. It really validated the time it took us to do the reanalysis. Now, reanalysis is a regular part of our pipeline, and we find a ten to twenty percent rate of diagnosis upon reanalysis.
Sarah: What do you want to see in the field of rare disease diagnosis in the future?
Susan: I think as a lab, we really want to help determine how we can get the highest diagnostic yield for everyone. We want to stay at the cutting edge of genome sequencing while also figuring out where we get the highest yield. For example, long-read sequencing is definitely giving us higher diagnostic rates than short-read sequencing, but is that higher than reanalysis of older cases with new knowledge? I think we also need to explore other parts of the genome, too. We know that methylation changes and non-coding variants are involved in disease, but we have a lot more to learn about the human genome, and we’re investigating each case as it comes along to see what we can learn from it.
For the field as a whole, my dream is that we will find and understand all of the disease genes. And as we’re doing this, we must keep making those resources available so everybody can do this better, faster, and easier.
Sarah: What advice would you give someone who is interested in pursuing a career in genetics?
Susan: Never stop asking questions. Curiosity really drives everything that we do in science. I love asking questions when I am analyzing a genome, and that curiosity often pays off when I identify new variants. When I was younger, I asked questions, but never out loud. I’m sure I missed out on many learning experiences by being too embarrassed to ask questions.
Sarah: Thanks for telling me all about your career journey and your job at HudsonAlpha. What do you do in your free time?
Susan: In my free time, I love spending time with my family. I dabble in a lot of different hobbies: I love doing jigsaw puzzles, I am an avid reader, and I have a houseplant and succulent collection that I enjoy taking care of. My most recent hobby is watercolor painting, which I am really enjoying.
