A clinical genomicist harnesses team-based science to help rare-disease patients
Heidi Rehm convinced labs and scientists to work together and share data. This has helped many people with rare disease find answers.
In the two decades that Heidi Rehm has been a clinical genomicist, she’s accumulated a lot of stories. There’s a patient whose shortness of breath and thickened heart wall suggested a cardiac condition but genetic testing revealed a completely different diagnosis. There’s a newborn whose genomic testing revealed a mutation in BRCA2, a gene commonly linked to breast cancer, prompting family testing and a preventative mastectomy by his mother. And then there are the stories that Rehm especially likes to tell, about parents who’ve come to her concerned about a result from their prenatal testing — the parents she gets to reassure, with a body of literature behind her, that their children will be okay.
These stories and diagnoses, made possible by clinical genomics labs around the world analyzing DNA from patients and sharing their findings with each other to improve medical care, weren’t always so common. In 2002, when Rehm was building such a lab at Mass General Brigham, she quickly realized how siloed these labs were. Every time one found a genetic variant in a patient’s data, they’d search the literature to find evidence on whether that variant might be contributing to a disease.
But because most data wasn’t published and labs didn’t pool together data on genetic variants in a central place, researchers and clinical labs would often struggle to determine whether a variant from a single patient was causing disease.
“I realized I wasn’t the only one having this experience,” said Rehm, an institute member and co-director of the Program in Medical and Population Genetics at the Broad Institute of MIT and Harvard and an investigator and Genomic Medicine Unit director in the Center for Genomic Medicine at Massachusetts General Hospital (Mass General). “Every genetic testing lab, every research study, everyone was experiencing this.”
Today, thanks in large part to several efforts spearheaded by Rehm over the last two decades, clinical genomics labs across the US and around the world routinely share data and findings. This has enabled geneticists to pinpoint the genetic cause of rare disease for more patients, providing a potentially life-changing source of relief, community, and sometimes even treatments for families struggling with often severe and deadly illnesses.
And though there is still a long way to go — about half of rare disease patients remain undiagnosed — Rehm’s fingerprints can be found on many of the standards and tools that have allowed clinical geneticists to increase their diagnostic success rate over the last 20 years. She led groups that developed a consistent language that scientists and clinicians everywhere use to interpret genetic variation the same way, and helped build a database used by every clinical lab in the world to return more results to more patients. A skilled organizer and community-builder, Rehm has helped change the culture in clinical genetics, showing labs the value in data-sharing and helping them to implement it in a consistent way. She has been a key player in ushering in a new era of collaboration, in which each lab has at its disposal the knowledge of other labs.
“Heidi is a true force to be reckoned with: When she has an idea, or more — an ideal, she will push until she sees it through. But she also has such positivity and takes everyone on the journey with her, making sure they see the value of her vision,” said Nicola Whiffin, an associate professor at the Big Data Institute in Oxford, UK who collaborates with Rehm as a visiting researcher. “That’s what makes her so convincing. I don’t think anybody can really argue with Heidi.”
Rehm’s clinical work and research inform each other: Not only has she helped return diagnoses to thousands of rare-disease patients, but she has also contributed to the discovery of hundreds of new disease genes.
“Heidi has really changed the world for rare-disease patients,” Whiffin said in 2022 when she introduced Rehm as a recipient of the Curt Stern Award from the American Society of Human Genetics, which recognizes scientists who have made remarkable contributions to the field over the past decade. “Her impact on the genomics field simply cannot be overstated.”
At the Broad, Rehm wears many hats: chief medical officer for Broad Clinical Labs, a co-leader of Broad’s Center for Mendelian Genomics, and head of the Translational Genomics Group, a research effort that aims to understand the genetic basis of rare disease. She is also the chief genomics officer at Mass General and a professor of pathology at Harvard Medical School. Outside her home institutions, she has leadership roles in the Global Alliance for Genomics and Health (GA4GH), the Matchmaker Exchange, The AllofUs Research Program, and the Genome Aggregation Database (gnomAD) — all of which, she says, address the same goal.
“Every step I’ve taken over the years — every grant I’ve applied for and role I’ve played — has been about delivering better care to patients,” Rehm said. “There are so many inefficiencies in how we learn about a person’s genetics, and that’s not all going to change overnight. But gathering the collective intelligence, drive, and effort of the community is going to allow us to do something that is greater than the sum of its parts.”
Roots of an organizer
As a child growing up in Lake George, New York, Rehm was ambitious and active, a good student and athlete who spent her free time hiking, canoeing, and camping in the Adirondack mountains. Her father, a high school biology teacher, filled their house with snakes and frogs he brought home from school over the summer. Her mother liked to get things done and made lists for everything, a trait both Rehm and her sister inherited.
From her first biology course in high school, Rehm loved the logic of genetics: the clear trajectory from a simple code of DNA to RNA to proteins — and how disrupting that process could lead to disease. In 1993, after earning a bachelor’s degree in molecular biology and biochemistry from Middlebury College, Rehm moved to Boston to pursue a PhD in genetics. At Harvard Medical School, Rehm joined the lab of Cynthia Morton, studying the genetic basis of hearing loss, and later the lab of David Corey as a postdoctoral fellow.
Even as a graduate student, Rehm was already showing her penchant for organizing and bringing people together. She formed the Division of Medical Sciences Mountain Club and organized outdoor adventures for other graduate students, and persuaded companies to donate medical supplies to families in need in Costa Rica when she’d traveled there for research.
In 2002, as Rehm was beginning her postdoc, Raju Kucherlapati, a colleague at Harvard, asked her to start a clinical lab at what was then called the Harvard-Partners Center for Genetics and Genomics that would do genetic testing for people with disease and help determine the cause of their conditions.
It was a chance to fulfill her dream of helping patients. “I wanted to catalog every rare disease and all the underlying disrupted genes,” remembers Rehm. “I wanted to make a difference for patients.”
When she took the position to build the Laboratory for Molecular Medicine at Mass General Brigham, Rehm also enrolled in a two-year fellowship program to become board-certified as a clinical laboratory geneticist. She and her growing team developed novel genetic tests, and soon, the lab was returning a range of information to patients, from the cause of childhood hearing loss or adult-onset cardiac disease, to how the genetic makeup of a person’s tumor might impact their response to different drug treatments. The lab supported clinical trials for newborn genome sequencing and whole genome sequencing in the routine care of healthy adults. Rehm ran the Laboratory for Molecular Medicine for 16 years, growing it from a team of one to more than 50 staff members who provided genetic testing for thousands of patients each year.
When she’d agreed to start the lab, Rehm thought that she would be putting research aside to pursue clinical work, and had made peace with that. But as she and her colleagues began identifying new genetic variants associated with disease, Rehm realized they should be sharing their findings with the research community to help drive scientific discovery.
“Over time, we were discovering new things during the course of clinical testing, defining the variation associated with disease,” she said. “As the NIH developed funding opportunities in genomic medicine, we started using that expertise to apply for grants and publish our findings to get them out to the community.”
She and colleague Daniel MacArthur started the Center for Mendelian Genomics (CMG) at the Broad in 2015, now part of the Translational Genomics Group (TGG), co-led by Anne O’Donnell-Luria, Kaitlin Samocha, and Monica Wojcik. The CMG studies the genetics of rare disease, bringing researchers together from around the world and developing new methods to uncover causes of disease. The TGG has demonstrated the value of genome sequencing for finding answers for patients with rare disease, developed a tool for diagnosing spinal muscular atrophy in different kinds of sequencing datasets, launched a platform called seqr to aid collaborators around the world in making genetic diagnoses for patients and sharing data, and has shown that genetic tests return more inconclusive results in individuals from underrepresented backgrounds. MacArthur and Rehm also started the Rare Genomes Project, which recruits and works directly with patients to uncover the genetic roots of rare disease.
Another key part of Rehm’s work is Matchmaker Exchange, which helps researchers to identify genes potentially connected with rare disease in patients and to connect with other patients worldwide who have the same symptoms and genetic signatures. This platform has led to thousands of novel gene discoveries and helped many patients arrive at a diagnosis after many years of searching.
“There’s a clear vision of what makes something a Heidi Rehm project — she’s really focused on using data sharing to improve science, and making sure that our work isn’t just going to help our team, but will also have a worldwide impact,” said Anne O’Donnell-Luria, who works with Rehm in Translational Genomics Group and is a co-director of the Center for Mendelian Genomics at Broad.
“No person can do all of that on their own, but Heidi has built a network of people here who embrace that vision and want to be part of it.”
A common language
As Rehm was building the Laboratory for Molecular Medicine, she put her community-building skills to work. In collaboration with the National Center for Biotechnology Information (NCBI) at the National Institutes of Health, she developed a multi-pronged approach to convince labs — including many that were for-profit — to share the associations they found between genetic variation and disease. She gave an early set of labs grant support to work with the NCBI to format and share their data in a standardized way. NCBI then launched the ClinVar database in 2013 to house that information in a public archive. Many other labs realized the benefit of sharing genomic knowledge to improve the efficiency of their work and make more diagnoses for patients, and soon followed suit.
Rehm also got on the phone with insurance companies and persuaded them to reimburse only labs that were sharing their data, which helped persuade a few labs that hadn’t yet prioritized data-sharing to get on board. Today, ClinVar has become the primary resource for defining the clinical significance of human variation, and is used by labs worldwide to both access and share genomic knowledge. “It was kind of inconceivable that somebody could get the laboratories to do this,” O’Donnell-Luria said. “But that was Heidi’s vision and mission and she pulled that off.”
Rehm and several groups funded by the National Human Genome Research Institute also teamed up to create the Clinical Genome Resource (ClinGen) in 2013, which helps define which genes and genetic variants are relevant for human health. Today, the program supports more than 100 panels of experts that evaluate evidence on the role of genes and variants in disease. ClinGen panels have classified the pathogenicity of over 8,800 genetic variants and evaluated over 3,000 genes for their connections to disease.
She also helped develop standards and guidelines for the American College of Medical Genetics and Genomics outlining how clinical labs should interpret genetic variants, so that every lab would speak the same language and operate consistently. Rehm and others continue to improve these guidelines. In 2023, she found that a third of all tests run in the US return inconclusive results due to variants of “uncertain significance,” and is working on defining sub-tiers of variants that could improve how patients and physicians manage genetic test results.
“This is really underappreciated and impactful work, because everyone needs rules to communicate clearly,” said Morton, Rehm’s PhD mentor, who has noticed the same inconsistent nomenclature in her own field of cytogenetics. “There are many people out there who are waiting for a diagnosis. Once they have that and can be in a parental support group or a clinical trial, their lives are changed. That wouldn’t happen without consistent variant interpretation.”
Building bigger networks
Rehm is now building on these approaches to help deliver better care to more patients in the US and abroad. She has long worked with international partners, now as chair of the Global Alliance for Genomics and Health (GA4GH), an organization that has spent the past decade building standards for structuring and sharing genomic data around the world.
But sharing data across country borders can be challenging because data — particularly individual patient information — often cannot leave the country due to privacy and funding concerns.
To overcome this hurdle, Rehm is collaborating with colleagues to advance the next version of the Genome Aggregation Database (gnomAD), which aggregates sequencing data from around the world and is used by scientists and clinical labs to understand which genetic variants are involved in disease. Rehm and collaborators are working on a federated version of the database. She is sharing the team’s methods for processing, analyzing, and controlling the quality of large genomic datasets with researchers in Africa, Australia, Brazil, Canada, China, Germany, Japan, Qatar, Singapore, Taiwan, the United Kingdom, and other locations. Each country will then share aggregated rather than individual-level data, capacity building and allowing their data to benefit both their local and the global community.
Similarly, Rehm is also developing a new kind of data-matching to boost the chances of getting a diagnosis for the 50 percent of rare disease patients who still remain undiagnosed. This work is modeled after Matchmaker Exchange, co-led by Rehm, which connects patients who have the same or similar genetic variants and disease symptoms to help physicians make diagnoses. But this effort matches patients by gene or variants in that same gene, which is only effective if the person conducting the search knows which genetic variant is linked to a patient’s disease.
So Rehm is helping to develop a more powerful version of Matchmaker Exchange, which would match patients according to their raw genomic information rather than specific genes. This could potentially enable more diagnoses for patients by connecting patients based on genetic variants that haven’t yet been identified as a candidate for disease. This infrastructure will connect entire databases so that researchers can look for matches in other databases without downloading data, which creates privacy concerns. She’s currently working with over a dozen groups around the world to connect their databases in this manner.
“There are a lot of challenges and bumps in the road ahead of us to actually build these tools and platforms,” Rehm said. “But there are incredibly committed groups that are excited to do this, because they see its value. Every genetic testing lab, every research study — everyone is experiencing these issues, and I think these kinds of efforts are going to be instrumental in making a major change that will improve the lives of countless patients.”
