Rethinking rare disease: How the ART Initiative is connecting genomics, the clinic, and the lab bench for RASopathies

The RAS Dialogue Blog posts are written by RAS experts sharing the latest research, updates, and scientific RAS news. The content is curated by the RAS Initiative.

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Pathogenic variants in RAS genes drive more than 20% of adult cancers and some of the most aggressive pediatric tumors. But RAS mutations don't only show up as acquired, sporadic events in tumors. Some people are born with germline changes in RAS pathway genes, and the result is a group of conditions called RASopathies.

RASopathies include Noonan syndrome, neurofibromatosis type 1 (NF1), cardiofaciocutaneous syndrome, Legius syndrome, and Costello syndrome, among others. Individually, each is rare. Collectively, RASopathies affect roughly 1 in 1,000 newborns, making them among the most common genetic syndrome groups in medicine. People with RASopathies can have life-threatening congenital heart disease, developmental differences, or an elevated risk of cancer. For years, no dedicated medical therapy for most RASopathy manifestations has existed.

However, that is starting to change, and a lot of the momentum is coming from an NCI initiative called ART: Advancing RAS/RASopathies Therapies.

A model that already worked — now scaled up

ART's origin story starts with a success. Dr. Brigitte Widemann and her team at the NCI's Center for Cancer Research (CCR) had already shown that a natural history study paired with early-phase trials could translate directly into approved therapy. Their work led to selumetinib, a MEK inhibitor, becoming the first FDA-approved treatment for NF1-related plexiform neurofibromas (PMID: 32187457).

Around the same time, Dr. Douglas Stewart and his team in the NCI's Division of Cancer Epidemiology and Genetics (DCEG) were pioneering a different approach to rare disease, termed “genotype-first”. In this strategy, applied to conditions like DICER1-related tumor predisposition (PMID:39070603), exome data is reviewed from large biobanks linked to electronic health records. It offered something the clinic-first model couldn't: a way to evaluate the full spectrum of a condition's effects. The approach includes people who have never been formally diagnosed and allows the calculation of true cancer risk, rather than risk estimates skewed by only studying the most severe cases, those who are reported in the literature or those who present to a clinic.

In 2018, investigators from CCR and DCEG realized these two approaches were stronger together than apart and founded ART, a cross-institute collaboration that brings genomic, clinical, and preclinical research together to advance RASopathies.

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Following patients over time

At the center of ART is a longitudinal cohort study, the Clinical, Genetic, and Epidemiologic Study of Children and Adults with RASopathies (NCT04888936), which opened for enrollment in 2021. Its central question: among people with RASopathies, who develops cancer, who doesn't, and what distinguishes them? The answer could reshape cancer screening guidelines for an entire patient population, and along the way it is building a far richer picture of RASopathy manifestations beyond cancer.

As of 2026, 86 affected individuals and 62 unaffected family members have enrolled, with 25 completing in-depth evaluations at the NIH Clinical Center and all participants completing questionnaires electronically from home. Dr. Gina Ney is leading this careful work, and it's already generating impactful results.

The first meaningful result from the longitudinal cohort study is a recognition that caring for a child with a RASopathy takes a toll on parents, too. That observation led Dr. Staci Martin and her team to pilot a remote therapy program for caregivers (NCT05361811), which proved to be feasible and promising.

The cohort is also starting to challenge assumptions about what a RASopathy diagnosis means for someone's cognitive outcomes. A recent case series drawn from the study's neuropsychological evaluations, led by Dr. Pamela Wolters, reported on three unrelated individuals with Costello syndrome, each carrying a different HRAS variant. Their cognitive profiles ranged from significant intellectual impairment to average and even high-average functioning. The findings push back on a common assumption in patient-facing materials that Costello syndrome uniformly involves intellectual disability and point instead to something more specific: outcomes appear closely tied to which HRAS variant a person carries (PMID: 41578731). This new information is exactly the kind of insight a natural history study is built to surface, and it's already reshaping how the team thinks about counseling patients and families about what to expect.

Several additional investigations within the cohort build on this approach, examining manifestations beyond cancer risk that affect day-to-day functioning and quality of life. One study, still unpublished, is examining bleeding risk ahead of surgery. Early analysis suggests Noonan syndrome carries meaningfully higher bleeding risk than other RASopathies. Two other efforts are underway: one examining sleep disorders across RASopathies, an area with little systematic study despite being a common concern, and another investigating body composition and metabolic health, tracking how RASopathies affect fat distribution and related metabolic measures. The team has also joined forces with Dr. Sarah Sheppard, an investigator in NICHD, on her effort to better understand the natural history of lymphatic anomalies (NCT05731141), which can occur in people with RASopathies.

Mining biobanks for answers hiding in plain sight

Meanwhile, ART's population genomics arm has been asking a different kind of question, using an entirely different kind of dataset: three of the world's largest biobanks, UK Biobank, Geisinger MyCode, and Mount Sinai BioMe, together representing genetic data from over 650,000 people.

By identifying RASopathy-associated variants in these populations, researchers can sidestep a persistent problem in rare disease research: ascertainment bias, in which studies only capture the most severely affected patients. The early findings are already surprising. Adult carriers of genetic variants associated with Noonan and cardiofaciocutaneous syndromes had no significant increase in cancer incidence. However, in the UK Biobank cohort, carriers of Legius syndrome showed an increased risk of cancer, specifically basal cell carcinoma, which could lead to a change in cancer screening guidelines for Legius syndrome (PMID: 41904680).

From mice and zebrafish to the clinic

A major strength of the ART Initiative is the ability to translate clinical work to the lab and vice versa. My team is testing potential therapies in mice carrying the Costello syndrome-associated HRASG12S mutation. New mouse models of Noonan syndrome are being developed to fill gaps that existing models don't capture.

Zebrafish are playing a role too: by expressing RASopathy-linked variants in developing zebrafish embryos, researchers can watch, in real time, how a mutation affects an organism's development — offering functional evidence for variants that genomic sequencing alone can't fully interpret. So far, Dr. Christine (Insinna) Kettenhofen and her team have functionally characterized several HRAS, MEK2, LZTR1, and SHOC2 variants (PMID: 42454412), work that feeds directly back into how these variants are classified in the clinic. Dr. Sarah Sheppard and her team study zebrafish RASopathy models to identify new candidate therapies (PMID: 37154160). 

None of this preclinical work happens in isolation. ART has forged a close collaboration with the NCI RAS Initiative, whose investigators have supplied key reagents and helped run experiments using techniques like fluorescence microscopy and NanoBRET, a method for studying protein interactions in living cells. That partnership has already led to new biological insights into how both newly discovered and previously studied HRAS variants actually function at the molecular level in Costello syndrome. These kinds of mechanistic details help explain why some variants produce a more severe disease course than others, and can identify which existing RAS-targeted therapies might be worth testing next.

What comes next

In ART’s next phase, the natural history study itself is set to grow well beyond the NIH's walls: plans are underway to expand it into a multi-site effort. That expansion should substantially accelerate enrollment while also reaching a more diverse and geographically distributed patient population. The multi-site evaluations will focus on RASopathy manifestations that remain poorly understood and potentially treatable, including bone issues, bleeding abnormalities, and cardiac disorders, which affect roughly half of people with RASopathies. That work matters beyond simply filling in gaps in the literature: many of these understudied features are exactly the kind of clinically meaningful, measurable manifestations that could serve as endpoints for future interventional trials, giving researchers a way to test whether a therapy actually treats something that improves the lives of patients and their caregivers. 

What makes ART distinctive isn't any single result — it's the architecture connecting population genomics, longitudinal patient follow-up, and laboratory models into one continuous loop. A variant identified in a biobank can be functionally tested in a zebrafish; a symptom flagged in the clinic can be checked for prevalence across hundreds of thousands of genomes; a mouse model's response to a drug can inform a clinical trial design. It's a small field, tackling a common disease group, using tools built for scale.

The ART Initiative is a collaboration between NCI's Center for Cancer Research and Division of Cancer Epidemiology and Genetics, developed in partnership with the patient advocacy group RASopathiesNet.

Interested in learning more or participating in the RASopathies natural history study?

Visit rasopathies.cancer.gov for more information.

Want to connect with the broader RASopathies community? 

Visit RASopathiesNet to learn more, including about the 10th International RASopathies Symposium, taking place in Indianapolis, IN from July 17–19, 2027.

If you're interested in participating in the dialogue, consider joining RASLab. RAS Lab is an online discussion forum to facilitate the exchange of scientific information among researchers in cancers related to RAS. If you would like to join RAS Lab, send an email to SolveRAS@nih.gov with the subject line "I would like to join RAS Lab."