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Rare and orphan disease research is evolving rapidly, driven by continued advances in genomic technologies and data interpretation. From long-read sequencing to structural variant detection and automation, these tools are reshaping how clinicians and researchers identify disease-causing variants. Historically, rare disease research has received less funding and attention, in part because each condition affects a relatively small proportion of the population. However, advances in genetic testing technologies have made rare disease research more feasible and increasingly affordable.
Psomagen recently had the opportunity to speak with Dr. Catherine Brownstein, a rare and orphan disease researcher and long-time Psomagen customer. Dr. Brownstein is an Assistant Professor of Pediatrics at Harvard Medical School, Research Associate in the Division of Genetics and Genomics at Boston Children’s Hospital, and Assistant Director of the Molecular Genetics Core Facility. With a career spanning the early days of clinical sequencing to today’s cutting-edge platforms, Dr. Brownstein brings a unique perspective on how genomics has transformed rare disease discovery, and where it is headed next.
From Environmental Health to Human Genetics
Initially interested in environmental health, Dr. Brownstein entered the field of genetics somewhat unexpectedly during her graduate training. “I kind of fell into it,” she recalls. When her PhD program professor left the institution, “The public health school said, ‘Well, we don’t really have a place for a PhD student. Maybe you should go to genetics.’ And long story short, I ended up in genetics and loved it.”
Her early research experience highlights just how dramatically the field has changed. During her PhD, Dr. Brownstein mapped a chromosomal translocation using BACs and Southern blots, a project that took six years and, as she notes, “could be done in three days now.”
The rapid development of sequencing technologies and other tools has advanced human health research and care. After her PhD, Dr. Brownstein joined Boston Children’s Hospital, where “I was actually hired to help researchers and clinicians get their samples sequenced with the goal of having every child who walks into the hospital have a sequence.” While that vision is still a work in progress, she notes that the field is steadily moving closer. Projects conducted through the hospital have led to recent papers published in all major journals. A recent publication entitled Interstitial Cystitis: a phenotype and exome sequencing study is just one example that showcases Dr. Brownstein’s impact on the field of gene discovery.
Supporting Hospital-Wide Genomics Through the Core Facility
In addition to running her own research group focused on rare disease genomics, Dr. Brownstein serves as Assistant Director of the Molecular Genetics Core Facility at Boston Children’s Hospital. In this role, “I get to facilitate sequencing for the entire hospital and really help them achieve their research goals, which is extremely rewarding and very fun.”
This dual role allows Dr. Brownstein to remain at the forefront of technological change while enabling discovery across a wide range of pediatric research programs. “That’s one of the best parts of my job,” she explains. “I get to stay really current on what’s up and coming — and sometimes try it out — because we have to know. We have to be aware of options for our researchers.” Dr. Brownstein has extensive experience evaluating and implementing new genomic platforms; two areas where she sees a lot of change and possibility are in single-cell sequencing and long-read technologies.
In testing new long-read technologies, she’s uncovered genetic variations undiscoverable with short-read sequencing. “It’s always interesting when you see something that’s not in the reference genome,” she says. “You don’t know if it’s platform-specific or if it could actually be disease-causing. It’s kind of like going back to 2010 when we were looking at the first sequences, and the databases of controls were like 200.”
She describes a compelling example from a case of hypophosphatemic rickets, where an insertion detected years earlier by optical mapping could not be validated at the time. “We couldn’t PCR across the insertion, so we couldn’t see if it was real or not.” Years later, the same variant reappeared in new data on the Nabsys OhmX platform and was ultimately confirmed using Nanopore sequencing—the variant was “clear as day” in both the patient and one parent. Despite its clarity in long-read data, the variant is absent from reference genomes, underscoring a major challenge in rare disease interpretation and a need to continue building out high-resolution reference data.
Proteomics, Robotics, and Technology Trends
Dr. Brownstein has also collaborated extensively in proteomics, and also highlights the importance of being embedded in a research environment like Boston Children’s Hospital. “I’m really lucky being here. A lot of times when you want to get into a technology, there’s someone who developed it within a stone’s throw.” She cited work with Dr. Hanno Steen, one of the greats in proteomic technologies, who is “right across the street” at Boston Children’s. This proximity enables rapid collaboration and experimentation, allowing new methods to be evaluated and adopted more quickly.
Looking ahead, one area Dr. Brownstein is particularly excited about is laboratory automation. Recent advances in robotics, she says, have focused on ease of use—lowering the barrier for adoption. “Robots were kind of the same for years and years,” she explains. “All of a sudden, they’ve realized that the barrier is the ease of use, and now I really want a new one. How awesome would it be if investigators could easily program a robot to take some of that human error out of their protocols?”
New systems allow researchers to program automation for small batches of samples, rather than requiring massive throughput to justify the effort. “That would be a total game changer,” she says, noting that even small reductions in manual pipetting can significantly reduce human error and improve reproducibility.
Large-Scale Sequencing for Underrepresented Populations
One of Dr. Brownstein’s major ongoing projects using Psomagen services is the NIH-funded Genetic Architecture of Early-Onset Psychosis in Mexicans (EPIMex), a large-scale sequencing study focused on early-onset psychosis in Mexican children. The project addresses both a critical clinical need and a significant gap in genomic reference data.
“This is an extremely serious disorder that needs a lot more understanding of the pathology, and doing large scale sequencing studies is the way to get at that,” she explains. Individuals of Mexican ancestry remain underrepresented in genomic databases, despite being one of the fastest-growing populations in the United States.
“Saying you’re Mexican is like saying you’re American,” says Dr. Brownstein, “in that there’s a lot of variability that goes into being Mexican.” In a highly complex, growing population, this project is “extremely timely, and we’re really excited to be working with Psomagen on getting the sequencing done.” By generating high-quality sequencing data at scale, the EpiMex project aims to improve disease understanding while contributing to more inclusive genomic resources.
A Longstanding Partnership in Genomic Discovery
Dr. Brownstein’s collaboration with Psomagen spans many years, dating back to its earliest days. Over the course of her career, she has relied on sequencing services to support both clinical research and gene discovery—including her first-ever identification of a de novo variant, found in KCNA1 in a patient with episodic ataxia.
“I remember exactly where I was when I saw it,” she recalls. Moments like these, she says, underscore the impact of reliable sequencing and long-term partnerships in advancing rare disease research.
Dr. Brownstein’s work exemplifies the intersection of technology development, clinical application, and collaborative research. From early sequencing efforts to today’s long-read and structural variant analyses, her career reflects the rapid evolution of genomics and the continued need for thoughtful interpretation, better reference resources, and accessible tools.
