Solving the Unsolved Cases of Rare Diseases

Q&A With Dr. Cláudia Carvalho: Solving the Unsolved Cases of Rare Diseases

Cracking the code of rare genetic diseases takes more than just science—it takes passion, collaboration, and a deep commitment to discovery. This is the work of Dr. Cláudia Carvalho and her team at PNRI.

With a focus on genetic structural variants that often go unnoticed in standard genetic tests, Dr. Carvalho’s lab is making strides in diagnosing rare diseases that have long baffled the medical community. From tackling complex neurodevelopmental or bone malformation conditions like MECP2 duplication syndrome and Robinow Syndrome to collaborating with international research teams, her work is pushing the boundaries of what’s possible in genetics.

We spoke with Dr. Carvalho about her groundbreaking research and what the future holds for patients with rare diseases. Here’s what she had to say.

Q: What is the focus of your lab? 

My lab studies structural variants in the genome and their role in rare genetic diseases, especially those affecting children. In the U.S. alone, around 12 to 15 million children live with rare diseases, most of which are genetic. Despite these large numbers, millions of them remain undiagnosed, and the molecular causes of many genetic diseases are still unknown.

One of the challenges lies in structural variants, which are changes in the DNA that can involve extra copies of genetic material, missing pieces, or even segments of DNA being flipped or rearranged. These variants are tricky—they don’t appear on most genetic tests, so we have to dig deeper in DNA sequencing to find them. 

My lab’s goal is to improve diagnostics by understanding how these variants contribute to rare diseases. Getting a diagnosis for a rare disease can be an incredibly long and frustrating process. It’s often called a “diagnostic odyssey” because it can take years—sometimes even decades—to discover what’s causing a patient’s symptoms. Our research aims to shorten that journey and shed light on the causes of rare diseases by applying the latest innovative technologies.

You can’t underestimate the power of a precise diagnosis—it opens doors to targeted treatments, clinical trials, and support networks that significantly improve the quality of life for patients and their families. It also allows families to access genetic counseling, helping them understand whether other family members may be at risk. A diagnosis opens the door to hope and resources.

Q: What recent discoveries from your lab are you most excited about?

We’re pushing the boundaries of how we understand genetic disorders. Our current projects are helping to improve unsolved diagnoses and have the potential to guide future therapies.

One example is our efforts to investigate the DNA structures that affect the expression of the MECP2 gene.  Increased expression leads to MECP2 duplication syndrome, while decreased expression leads to Rett Syndrome—both of which are severe neurodevelopmental disorders.  Learning how the gene structure is altered in a patient is crucial for developing the proper therapy to adjust the gene’s expression level.

Another exciting area we’re focusing on is a specific genomic rearrangement called the DUP-TRP/INV-DUP structure, often seen in neurodevelopmental disorders. Even though it’s rare, this structure is found in around 26% of certain disease cases, making it a key factor in both genetic disorders and common diseases like cancer. Scientists have long suspected there are four sub-structures within this variation, but no one had confirmed it—until now.

Using advanced long-read DNA sequencing, we found evidence for all four sub-structures and pinpointed where the genetic sequences fuse. This breakthrough allowed us to create a prediction model to understand how each of these structure forms. By studying their subtle differences, we hope to predict disease severity and improve patient care.

We’re also delving into rare genetic inversions—when sections of chromosomes flip and reintegrate. These can be tough to detect but have serious consequences for gene function. In fact, we recently resolved three cases involving these inversions, including one tied to Kleefstra syndrome, a rare neurodevelopmental disorder.

In August, I had the opportunity to present at the Forbeck Forum, where I shared our findings on complex genomic rearrangements and inversions with cancer researchers. These mechanisms play a key role in cancer development, and it was exciting to discuss how they might lead to new insights in diagnosis and treatment. Meetings like this are invaluable because they allow us to share data, learn from one another, and spark collaborations that can push our research forward. 

Additionally, we’ve been investigating rearrangements on specific chromosomes, like chromosome 21, which plays a role in conditions like cancer, Alzheimer’s, and Down syndrome. We’re using genome mapping to explore previously hard-to-study regions, uncovering how certain structures contribute to these diseases.

Q: How does working at an independent research institute benefit your work? 

Being at PNRI gives me the freedom to explore complex and challenging research questions without the constraints that might exist at larger institutions. I can pursue open-ended research on diseases that are difficult to diagnose and have no effective treatments, and I have the flexibility to collaborate with other researchers across the globe. 

Seattle is an ideal location for this work. It’s a hub for healthcare and technology, which has allowed us to build strong partnerships with institutions like the University of Washington, Seattle Children’s Research Institute, and Fred Hutchinson Cancer Center. These collaborations are crucial for tackling the complexities of rare diseases. 

One great example of our collaborative efforts is PNRI’s upcoming Rare Disease Day 2025 symposium on February 28, 2025, where researchers, clinicians, and patient advocates will come together to discuss the latest breakthroughs in rare disease research. Hosting events like this allows us to advance the collective understanding of rare diseases. It’s a chance to share ideas, foster new collaborations, and ultimately make progress toward better diagnostics and treatments.

Q: How is your lab impacting science and medicine right now?

Structural variants are still a poorly understood area of genetics, but our lab is making significant strides in this field. We use advanced techniques like long-read DNA sequencing to detect these variants, which has already led to a better understanding of how they influence health. This knowledge is helping doctors make more accurate diagnoses, which is critical for providing patients with the best possible care. 

Our research also plays a crucial role in identifying which patients might do well in a clinical trial by providing a clearer picture of the genetic and biological mechanisms underlying a disease. Through our research, scientists can identify specific genetic mutations or biomarkers that indicate how a patient’s body might respond to certain treatments.

What’s particularly exciting is how rare disease research is driving a revolution in medical science. As we dive into these genetic intricacies, we’re not just uncovering new knowledge but actively contributing to groundbreaking approaches. For instance, the insights we gain into structural variants are paving the way for innovative gene therapies like CRISPR and opening doors to drug repurposing strategies. In many ways, our work is at the cutting edge of this transformation, helping to push the boundaries of what’s possible and improving the lives of affected children and their families.

Q: How will people in the future benefit from this research?

One of the most exciting aspects of our work is how it fits into the broader rare disease community, which is both vast and highly collaborative. Families play a critical role in this field—they are often the ones pushing the boundaries and bringing together scientists to move research forward. 

For example, we’ve seen incredible efforts from families like those involved with the FAM177A1 Research Fund, who are driving research on newly discovered genes that were previously unknown to cause disease. These families work with large research consortiums to identify the genetic alterations causing their children’s conditions, and in turn, this data enriches global databases that researchers use to interpret genetic variants.

As we study more rare diseases, we begin to see patterns. Discovering how a genetic alteration affects one disease can provide insights into other diseases that share similar pathways or mechanisms. This cumulative knowledge accelerates progress across the board, which helps us to develop solutions that can help more patients. 

Q: How does collaboration play a role in your work?

Collaboration is absolutely essential in rare disease research, including international collaboration. These conditions are so complex and varied that no single lab or country can tackle them alone. By working together, we can share data, resources, study findings, and expertise, which accelerates our understanding of rare diseases and brings us closer to finding solutions.

One example of this kind of collaboration is a recent hackathon we hosted at PNRI, which brought together researchers from the Karolinska Institute in Sweden and  Baylor College of Medicine and Seattle Children’s. For three intense days, we worked in groups to address specific problems related to copy number variants—a type of structural variant that can be involved in rare diseases. 

The hackathon was incredibly rewarding! It was fascinating to see how everyone’s expertise came together to address these complex challenges. We made some important breakthroughs that we wouldn’t have achieved without this collaborative environment. 

This need for collaboration is also the reason behind why we created PNRI’s Science Matters Seminars. These are free, virtual seminars, where scientists from all over the world share and discuss exciting research in genetics, genomics, and evolutionary biology. We cover a range of topics, including the genetics of ethnically diverse populations, diseases affecting vulnerable or underserved groups, and efforts to expand the diversity of research subjects and the scientific workforce.

The seminars are open to the scientific community and anyone interested in learning more about genetics. By connecting researchers, students, and the public through these seminars, we’re not just sharing information—we’re building a global community dedicated to advancing our understanding of genetics and its impact on society.

Beyond these events, my lab is also a partner in GREGoR (Genomics Research to Elucidate the Genetics of Rare disease), which is a consortium funded by the National Human Genome Research Institute. This consortium focuses on developing and applying new approaches to uncover the causes of unexplained rare genetic disorders. Being part of such a global effort allows us to combine our strengths with other leading researchers, which is vital for making progress in this challenging field.

For me, science is a deeply social experience. It’s about collaboration, brainstorming, and working together to solve complex problems. Whether it’s through international partnerships, collaborations with patients and their families, or events like the hackathon, Science Matters seminar series, or Rare Disease Day—the collaborative nature of science is what gives my work purpose and makes those “this is why I became a scientist” moments so fulfilling.

Q: How does philanthropy support your work?

Philanthropy plays a crucial role in advancing our research. Rare diseases don’t receive the same level of federal funding as more common conditions, so philanthropic support helps fill that gap. It allows us to take risks, explore new ideas, and develop innovative approaches that might not be possible otherwise. This kind of support is vital for pushing the boundaries of what we know and finding solutions for families who are desperately searching for answers.

Q: What do you think the future holds for rare disease research?

The future of rare disease research is incredibly promising. Over the next decade, I believe we’ll see significant advancements in our understanding of the genome, particularly in the more challenging regions of DNA, and how these variations cause different diseases. With new technologies like CRISPR and advanced gene therapies like antisense oligonucleotides (ASOs), we’re likely to see more treatments reach clinical trials and gain FDA approval.

One of the most exciting areas is the link between precision diagnostics and precision medicine. As we get better at pinpointing the exact genetic mutations behind rare diseases, we’ll be able to develop more targeted, personalized treatments. This means that instead of a one-size-fits-all approach, treatments will be tailored to the specific genetic profile of each patient, leading to better outcomes and fewer side effects.

Beyond the science, I’m hopeful that we’ll witness a stronger global collaboration in this field. Countries with fewer resources are becoming more involved through open-source initiatives and training programs. By working together and sharing knowledge, we can create a more inclusive global effort to tackle rare diseases, ultimately leading to better outcomes for patients everywhere. While there’s still work to be done, I’m optimistic about the progress we’ll make in the years to come.

Q: What do you like to do in your spare time?

I love exploring the world with my kids. We’re always biking, swimming, or doing anything outdoors—especially in the summer. Introducing them to new experiences is one of my favorite things. I also enjoy spending time with my family from Brazil and catching up with friends. Staying connected to loved ones is really important to me. And when I get some quiet time, I love diving into a good book!

Dive Deeper

Dive deeper into Dr. Carvalho’s work by listening to her podcast episode “Science is a Social Experiment”  (link coming soon!) Learn more about the Carvalho Lab and connect with PNRI to meet Cláudia and experience her groundbreaking science in person.