When cardiologist Dr. William J. Groh examined a young woman with an arrhythmia in 1995, he thought it was unusual. She did not have known heart disease or heart failure that would normally be associated with a serious heart rhythm disturbance. What she did have, though, was myotonic dystrophy (DM).

The case sent Dr. Groh searching through the available medical literature. At the time, it was not established that such heart complications were common among myotonic dystrophy patients. He found papers discussing the issue, but there were no large studies that sought to answer fundamental questions about cardiac involvement in myotonic dystrophy.

Dr. Groh, who was then a fellow at Oregon Health & Science University in Portland, OR, decided to undertake a large natural history study of myotonic dystrophy type 1 patients. The goal was to determine in the general myotonic dystrophy population what the risk of heart problems was, whether there were predictors of such problems that could identify patients at greater risk, and what could be done prevent some of the adverse outcomes.

When the 11th meeting of the International Myotonic Dystrophy Consortium (IDMC-11) convened in San Francisco September 5–9, 2017, Dr. Groh was one of the researchers who presented.

“It was an excellent meeting,” Dr. Groh said. “It brought together a world-class group of leaders in the research and care of myotonic dystrophy. Every disease should have this type of support. Researchers, clinicians, patients, and advocacy groups all get together in one meeting, so it’s very important.”

Among the issues of greatest concerns for Dr. Groh are the need for additional research to identify the best strategies for addressing myotonic dystrophy type 1 (DM1) patients at risk for sudden death from arrhythmias, and the need for employing interdisciplinary teams to address the complexities of health issues DM patients face.

Study Launched

In April 1997, after moving to Indiana University, Dr. Groh began work on a major natural history study of DM1 patients. At that time, he believed that efforts to determine how to identify DM1 patients who were at high risk for sudden death were stymied because the populations for previous studies were too small and not adequately representative of the broad DM1 population. As a result, he said it left unclear the best way to diagnose and treat DM1 patients at greatest risk of sudden death.

The study, which enrolled 406 patients at 23 neuromuscular disease clinics in the United States, was the first such study to use genetic testing to confirm that all of the participants had DM1. It showed that some adult patients with the disease were at high risk for sudden death. It also found that severe electrocardiographic (EKG) abnormality and a clinical diagnosis of a sustained atrial arrhythmia were independent predictors of sudden death.

“We showed that we could use a simple EKG to help determine who was at high risk for heart problems in myotonic dystrophy,” he said. “Our work allowed us to take a general myotonic dystrophy population and screen people.”

He said if a younger person with myotonic dystrophy came in and had a normal electrocardiogram and no other heart findings on examination, the chances that they would have a problem relating to their heart in the next five years would be low. However, if they had significant abnormalities on their electrocardiogram, it was a cause for concern.

Differing Opinions

French researchers, he said, had been doing excellent work in parallel with his study. However, their work supported a greater use of prophylactic pacemakers in patients before serious heart problems are manifest. Dr. Groh’s work also showed the value of pacemakers but questioned whether the risk of sudden death was still excessive despite the presence of a pacemaker.

In fact, Dr. Groh has raised the issue of whether an implantable cardioverter-defibrillator (ICD) that can act as a pacemaker as well as treat rapid ventricular arrhythmias would be a better way to protect patients. In a paper published in June 2008, his work suggested that patients might benefit from an ICD.

Nevertheless, Dr. Groh cautions that his study was observational and that the French studies carefully examined a high-risk population that received pacemakers and showed benefit. He believes the question of whether the use of a pacemaker or ICD would allow patients to live longer and live a better life remains unresolved. “That’s another study that needs to be done,” he said.

“I think the next important trial in the United States would look at a high-risk population of myotonic dystrophy patients and treat them with an ICD and look at outcomes,” he said. “What we have found so far is that many U.S. doctors are putting pacemakers and ICDs in patients with myotonic dystrophy and we’d like to show, in fact, exactly which patients can benefit from this.”

A Team Approach

Dr. Groh’s interest in arrhythmias comes naturally. As an undergraduate student at Marquette University, he majored in electrical engineering. Today, as a cardiologist, a cardiac electrophysiologist, a professor at the Medical University of South Carolina, and the chief of medicine at the affiliated Veterans Affairs Medical Center, he focuses broadly on patients with heart rhythm disturbances, not just patients with DM.

He said that many cardiologists do not understand heart involvement in myotonic dystrophy. They may see just one or two myotonic patients and may not recognize the relevant issues. Dr. Groh said he’s always happy to get on his “soapbox” to preach about the need for a team of specialists to care for myotonic dystrophy patients.

“Because so many systems are affected by myotonic dystrophy, when you are approaching these individuals you have to deliver multidisciplinary care,” he said. “The team should include a neurologist, a physical therapist, a pulmonologist because of lung involvement, and a cardiologist. Over the last decade, we’ve seen more of these multidisciplinary clinics set up and this is important for delivery quality care to DM families.”

Induced pluripotential stem cell (iPSC) technology has provided opportunities to better understand disease mechanisms as well as to facilitate drug discovery and development programs. With the attendant molecular, cellular, and disease backgrounds of readily expandable, patient-derived cells, iPSC “disease-in-a-dish” models have supported the translation of candidate therapeutics from discovery into clinical testing.

As long as limitations are recognized, such as potential genetic and epigenetic divergence from primary cells, iPSC modeling of myotonic dystrophy (DM) may be essential to mechanistic understanding and development of treatments for the disease, particular when patient tissues are difficult to impossible to access (e.g., CNS and heart). MDF has facilitated the development of human DM1 iPSC lines, now available through RUCDR Infinite Biologics, with DM2 lines to follow.

Development of iPSC-Derived Cardiomyocytes

Reported in a newly published study, Dr. Federica Sangiuolo (University of Rome Tor Vergata) and colleagues have developed iPSC lines from two DM1 patients and two healthy controls. They characterized cardiomyocytes derived from these lines, with the goal of determining whether they could recapitulate at least some of the major traits of the DM1 heart. Myocyte characterization included RT-qPCR to quantify RNA expression, FISH and IF for nuclear foci, RT-PCR for splice variants, whole-cell patch clamp to characterize cardiomyocyte electrophysiology, and atomic force microscopy (AFM) to characterize biomechanical traits.

Traits of iPSC-Derived Cardiomyocytes—DM1 versus Wild Type

Most iPSC-derived cardiomyocytes exhibited a ventricular-like phenotype. DM1-derived cardiomyocytes contrasted with wild type controls in expressing nuclear foci and mis-slicing of each transcript evaluated (MBNL1, MBNL2, TNNT2 and SCN5A); DM1 derivatives also showed down-regulation of key cardiac ion channel transcripts (CACNA1C, KCNH2, KCNQ1, KCND3, and SCH5A) compared with controls. The research team noted novel differences in nuclear morphology in DM1 derivatives, potentially related to altered expression of lamin A.

Whole-cell patch clamp recordings of disaggregated single cardiomyocytes showed an abnormal electrophysiological profile only in the DM1 derivatives. DM1 ventricular myocyte-like derivatives exhibited lower spontaneous action potential rates, lower peak amplitude, and longer time to reach peak from threshold. Electrophysiologic parameters of DM1 cardiomyocytes could be altered by drugs targeting cardiac ion channels.

Using AFM, the research team identified differences in beat frequency and synchronicity of beats in DM1 iPSC-derived cardiomyocytes—describing the overall pattern as indicative of instability, with reduced frequency and the appearance of non-synchronous oscillation patterns when compared to wild type. The predominance of ventricular-like myocytes, and relative absence of nodal or other conduction system-related cardiomyocytes, may make it more difficult for iPSC-based models to be informative of the conduction system-specific abnormalities known to characterize DM1.

Overall, DM1 iPSC-derived cardiomyocytes recapitulated the main morphologic and molecular markers of the disease, including CTG expansions, nuclear foci, splicopathy of the mRNAs evaluated, and altered expression of several known cardiac ion channels. Alterations in electrophysiological parameters and biomechanical behavior were interpreted as consistent with unstable beating.

Reference:

Modelling the pathogenesis of Myotonic Dystrophy type 1 cardiac phenotype through human iPSC-derived cardiomyocytes.
Spitalieri P, Talarico RV, Caioli S, Murdocca M, Serafino A, Girasole M, Dinarelli S, Longo G, Pucci S, Botta A, Novelli G, Zona C, Mango R, Sangiuolo F.
J Mol Cell Cardiol. 2018 Mar 15. pii: S0022-2828(18)30083-X. doi: 10.1016/j.yjmcc.2018.03.012. [Epub ahead of print]

Role of Muscleblind Proteins in Health and Disease

Muscleblind (MBNL) proteins play a central role in the pathogenesis of myotonic dystrophy (DM), as MBNL depletion below a threshold level triggers a range of mRNA splicing, polyadenylation, localization, and processing defects and, thereby, the production of temporally inappropriate protein isoforms. This compromise of function for a wide range of proteins, in turn, leads to the multi-organ system phenotypes that characterize DM. To understand MBNL’s roles in normal development and function, and dysfunction in DM, it is essential to elucidate mechanisms underlying its spatial and temporal localization and steps necessary for its functional activation/inactivation.

Dissecting the Role of MBNL in the CNS

Understanding the regulation and functional roles of MBNL proteins in the CNS represents a critically important problem in determining pathogenic mechanisms underlying the nervous system phenotype in DM. Dr. Guey-Shin Wang at National Yang-Ming University and Academia Sinica (Taiwan) have published an article in Cell Reports that MBNL1 localized to the cytoplasm, but not that retained in the nucleus, plays a key role in neurite morphogenesis and show that this role is disrupted in DM1.

Using FLAG-tagged isoforms of MBNL1 (with and without exon 5) expressed in hippocampal neuron cultures, Dr. Wang and colleagues demonstrated that MBNL1 that included exon 5 was retained in the nucleus and had no impact on neuronal development, while exon 5-deleted MBNL1, which translocates to the cytoplasm, enhanced dendrite and axon morphogenesis.

Consistent with this role for MBNL1 in regulating neurite differentiation and the differentiation failure in DM1, the research team showed that either MBNL1 knockdown or overexpression of 960-repeat DMPK mRNA (DMPK-CUG⁹⁶⁰) resulted in delayed neurite maturation. Moreover, the cytoplasmic (exon 5 deleted) MBNL1 isoform, but not the nuclear-localized isoform, was found to rescue maturation defects in neurons expressing DMPK-CUG⁹⁶⁰ in a dose-dependent manner.

Mechanisms Regulating Neuronal Subcellular Distribution of MBNL1

Analysis of the developmental distribution of the two MBNL1 isoforms led to the puzzling finding that nuclear or cytoplasmic localization was independent of exon 5 inclusion/exclusion, suggesting that another factor regulated MBNL1 localization in the developing brain. The research team then demonstrated that Lys 63-linked ubiquitination of MBNL1 and neuronal activity level regulated its cellular localization. Finally, it was shown that deubiquitination caused by expanded repeat mRNA resulted in a cytoplasmic-to-nuclear translocation of MBNL1 and corresponding alterations in neurite morphogenesis—these consequences were prevented by deubiquitination inhibitors.

Taken together, Dr. Wang and colleagues have shown that MBNL1 plays a key role in neuronal differentiation and that disruption of its cellular localization alters functionally significant steps in neuronal structure and function that likely underlie the CNS consequences of DM. Moreover, their identification of the regulatory role that the ubiquitination/deubiquitination status plays in the cytoplasmic localization of MBNL1 suggests a novel potential target for therapeutic development in DM1.

Reference:

Ubiquitination of MBNL1 Is Required for Its Cytoplasmic Localization and Function in Promoting Neurite Outgrowth.
Wang PY, Chang KT, Lin YM, Kuo TY, Wang GS.
Cell Rep. 2018 Feb 27;22(9):2294-2306. doi: 10.1016/j.celrep.2018.02.025.

The National Human Genome Research Institute (NHGRI) has issued two new Funding Opportunity Announcements in support of research to utilize a patient’s own genomic information to inform clinical care and health outcomes. These Announcements represent a potential opportunity to apply an understanding of the genomics of those living with myotonic dystrophy (DM) to clinical management and treatment settings.

The stated objective of the NHGRI program is to “stimulate innovation and advance our understanding of when, where and how best to implement the use of genomic information and technologies in clinical care in all populations.” The program utilizes both R01 (PAR-18-735) and R21 (PAR-18-736) grant mechanisms. R01 applications are limited to $500,000 direct costs/year and 4 years; R21 applications to $275,000 total direct costs over 2 years. The PAR designation implies that applications will be assigned to a dedicated study section (Special Emphasis Panel or other) for review; there are no set-aside funds designated for this initiative.

Eligible activities include, but are not limited to, research studies on genome sequencing for disease diagnosis, treatment, or healthcare utilization. Interested applicants should see the Program Announcements referenced above and are strongly encouraged to discuss plans for applications with the Program Director identified in the Announcements.

Meet one of our 2025 Pilot Grant Recipients, Kate Eichinger, PhD! Dr. Kate Eichinger has worked with people living with myotonic dystrophy (DM) for nearly two decades. Over this time, she has watched how this multi-systemic condition affects individuals as well as entire families. As a physical therapist in a multi-disciplinary clinic, she has sought to improve their day-to-day experiences and quality of life by providing recommendations that maximize strength, functional abilities, and independence while minimizing symptoms and secondary impairments.

As a clinical researcher, she has contributed to natural history studies by assisting with study design, outcome measure selection, data collection, analysis, and dissemination. She is also currently working to develop a remote intervention for individuals living with DM to increase engagement in physical activity and exercise, recognizing the role that physical activity and exercise play in overall health and wellness. Additionally, as a health care provider and advocate, she has contributed to developing care guidelines, sharing resources for the patient community regarding physical therapy, providing physical activity and exercise recommendations to patients, and participating in the Myotonic Dystrophy Foundation Movement Committee.

The study “Wearable Sensors to Monitor Gait and Balance in Individuals with Myotonic Dystrophy” seeks to fulfill a gap in understanding regarding gait and balance function in individuals with DM. Using wearable sensors to gather more precise information regarding gait and balance may provide opportunities for early detection of change. This knowledge may be used to improve clinical care and research for individuals with DM. It may allow clinicians to evaluate the impact of therapeutic interventions such as the use of ankle foot orthotics to address ankle weakness or foot drop, or balance training- thus having the potential to bring immediate improvement to a person’s mobility and quality of life.

Click here to learn more about MDF's research funding opportunities and prior grant recipients.

Meet one of our 2025 Pilot Grant Recipients, Juan Manuel Fernandez, PhD! Dr. Juan Manuel Fernandez is an experienced researcher with over 15 years of expertise in myotonic dystrophy (DM) research. His extensive knowledge spans key areas, including molecular pathogenesis, biomedical model development, identification of novel therapeutic targets, and drug discovery for myotonic dystrophy. In recent years, his contributions have significantly advanced the understanding of the role of microRNAs (miRNAs) in DM1, muscle atrophy, and autophagy. Notably, he has spearheaded the development of therapeutic approaches based on miRNAs, culminating in the ArthemiR™ clinical trial, now in Phase I/IIa.

He has led the innovative development of functional 3D skeletal muscle models derived from patient cells for various muscular diseases. These models include the first-ever 3D bioengineered model for myotonic dystrophy, which accurately replicates patient-specific muscle weakness and myotonia. This model is currently used in his laboratory to test potential therapeutic candidates for the disease.

In the Biomimetic Muscle Models for in vitro functional analysis and drug assessment in DM2 (BMM-2) project, the applicant aims to leverage his extensive expertise in myotonic dystrophy and tissue engineering to develop a novel model for myotonic dystrophy type 2 (DM2). This effort aligns with his longstanding commitment to advancing research in this field and addresses the critical need for robust DM2 models to facilitate drug development.

Click here to learn more about MDF's research funding opportunities and prior grant recipients.

Meet two of our 2025 Pilot Grant Recipients, David Housman, PhD and Christopher Ng, Sc.D.! Drs. David Housman and Christopher Ng are committed to advancing therapeutic strategies for DM1 by targeting the underlying mechanism of CTG repeat instability. The project “A Targeted DNA Repair Enzyme Therapy for Myotonic Dystrophy” represents a focused effort to expand a promising DNA repair enzyme therapy, developed in the context of Huntington’s disease (HD), into the DM1 field. The MDF pilot grant is essential to enabling this expansion and to initiating a strategic collaboration with Dr. Eric Wang, whose laboratory has been at the forefront of DM1 biology, model development, and therapeutic delivery.

Dr. Housman has had a long-standing and impactful career in DM1 and other repeat expansion disorders (REDs), including seminal contributions to uncovering the genetic underpinnings of DM1 and HD. Dr. Ng is a dedicated early-career investigator who has been working under Dr. Housman’s mentorship to develop FAN1 as a disease-modifying therapeutic for repeat expansion disorders. While Dr. Ng’s primary research has centered on HD, this proposal marks a committed pivot into the DM1 space. He is deeply invested in both the scientific and translational aspects of this research, including therapeutic development and commercialization.

The Housman Lab has a longstanding dedication to the genetic discovery and mechanistic understanding of inherited diseases, including its early co-discovery of the DMPK gene implicated in DM1. The team is fully committed to advancing this project as a sustained line of investigation into DM1 biology and therapy. With MDF’s support, they aim to catalyze not only preclinical discovery but also longer-term therapeutic development that will ultimately improve the lives of those affected by DM1.

Click here to learn more about MDF's research funding opportunities and prior grant recipients.

Bringing Myotonic Dystrophy into the Newborn Screening Conversation

On February 14, 2025, the RNA Institute and the Myotonic Dystrophy Foundation (MDF) organized and co-hosted the first ever symposium exploring how to include myotonic dystrophy (DM) in newborn screening. Newborn screening is one of the most successful public health services testing all babies shortly after birth for certain genetic, life-threatening diseases. Conditions included in newborn screening are serious and life threatening and without early diagnosis would result in irreparable harm and death. Conditions included in newborn screening are also diseases that do not have treatments but benefit from early disease management thereby significantly improving clinical outcomes. Newborn screening identifies babies at risk for these diseases before symptoms start, ensures the best possible outcomes for all babies, and limits pain and suffering.

Click here to download the agenda from the Newborn Screening & Sequencing for Myotonic Dystrophy Mini-Symposium 2025! >>>

Looking for more detail? Scroll down for scientific and expert-level summaries, including a Scientific Abstract and a deeper technical overview.

The Power and Promise of Genome Sequencing

The meeting brought together researchers, doctors, public health leaders, industry experts, and patient advocates to share progress in genome sequencing, diagnostic tools, and pilot newborn screening programs. Laboratory tests using genome sequencing allow the identification of a select set of genetic diseases based on changes in a person’s DNA. Diagnostic genome sequencing is a comprehensive genetic test performed in a specialized laboratory. The test analyzes an individual's entire genome or DNA to identify potential disease-causing changes. It is increasingly used to diagnose rare and inherited diseases, particularly when other tests are either inconclusive or simply not available. By examining the entire genome, the test can detect changes that might be missed by other tests, potentially leading to a faster and more accurate diagnosis. Although such tests could help diagnose babies faster and cut healthcare costs, obstacles for implementing the tests include high costs, limited state funding, and the lack of treatments for infants with DM. Experts also discussed ethical concerns—like testing infants for untreatable conditions—but noted that early detection of DM would allow for planning, including engaging in preventive and pre-symptomatic health measures such as regular cardiac monitoring, raise awareness of the serious impact of anesthesia, and would also support research.

Next Steps Toward a Future with Newborn Screening for DM

Participants recommended the following next steps: tracking DM patients over time, piloting health-record studies to identify patients with DM earlier, promoting testing and reimbursement policies, educating medical providers about genome sequencing-based testing and early diagnostics through newborn screening, exploring and advocating for the addition of DM in prenatal screens, and involving the community to build supporting data and resources needed for DM newborn screening in the future.

Thank You to Our Hosts and Organizers

Scientific Summary: Newborn Screening for Myotonic Dystrophy

Background: On February 14, 2025, the RNA Institute and the Myotonic Dystrophy Foundation held a mini symposium to discuss how myotonic dystrophy (DM) could be added to newborn screening. Newborn screening is one of the most successful public health services testing all babies shortly after birth for certain life-threatening diseases. Conditions included in newborn screening are serious and life threatening and without early diagnosis would result in irreparable harm and death. Newborn screening identifies babies at risk before symptoms start, ensures best possible outcomes for all babies, and limits pain and suffering. Methods: The meeting brought together researchers, clinicians, public-health leaders, industry experts, and patient advocates. They reviewed advances in genome sequencing, diagnostic methods, and early pilot newborn screening programs.

Results: Experts agreed that rapid genome testing could speed up diagnosis and help lower healthcare costs. However, several barriers were raised:

• High testing costs
• Limited state funding and a shortage of infrastructure and trained personnel performing genome sequencing based newborn screening
• No existing treatments for infants with DM

Ethical Discussion: Participants debated the ethics of testing newborns for still untreatable conditions. Despite these concerns, they noted that early detection helps parents prepare and supports research progress. Recommendations: The group proposed several action items:

1. Follow diagnosed infants over time
2. Conduct pilot studies using electronic health records to identify undiagnosed patients
3. Advocate for supportive policies and pilot studies ultimately enabling newborn screening for DM
4. Educate healthcare providers about DM screening and genetic testing solutions
5. Explore adding DM to prenatal screen panels
6. Engage families and communities to build support for the adoption of newborn screening for DM

Conclusion: While acknowledging financial, logistical, and ethical challenges, the symposium concluded that early detection of DM offers clear benefits. A coordinated strategy—combining research, policy advocacy, provider education, and community engagement—is essential for future implementation.
 

Full Technical Summary: Symposium on Genomic Sequencing and Myotonic Dystrophy

Summary of Newborn Screening & Sequencing for Myotonic Dystrophy

Newborn screening (NBS) is a vital and extremely successful public health program aimed at the early identification of conditions that can affect a child’s long-term health or survival. Early detection, diagnosis, and intervention – commonly before the onset of symptoms - can prevent death or disability, alleviate physical, emotional, and economic suffering, and enable children to reach their full potential. With the advancement of genomic sequencing technologies, there is growing interest and opportunity in expanding NBS to include a broader range of genetic disorders. This broadened scope includes conditions, like myotonic dystrophy (DM), for which early treatment may not yet be available but where early diagnosis can inform family planning, clinical monitoring, and guide future therapeutic development. The following summary synthesizes the discussion from a recent Myotonic Dystrophy mini-symposium hosted by the University at Albany’s RNA Institute and co-organized by the Myotonic Dystrophy Foundation and the RNA Institute. The following notes highlight the current state of the field, challenges, and future directions of NBS and genetic testing for DM.

Key Players weighed in on Newborn Screening

The discussions involved a diverse group of stakeholders from academia, industry, public health, and patient advocacy groups. Andy Berglund, PhD (Director, RNA Institute & Chair of Myotonic Dystrophy Foundation Scientific Advisory Committee) and Andy Rohrwasser, PhD, MBA (Chief Scientific Officer, Myotonic Dystrophy Foundation) co-organized and facilitated the meeting with key stakeholders in the field.

In a public session open to the community, key invited experts and opinion leaders summarized critical insights into NBS, myotonic dystrophy (DM), how NBS could be applied to DM, clinical and economic benefits supporting genomics based newborn screening, as well as technology opportunities today that could bridge until genomic NBS solutions would become available.

• Introduction to Myotonic Dystrophy and Therapeutic Landscape; Andy Berglund, PhD; Professor, Director of the RNA Institute, Co-Director, Center of Excellence in RNA Research and Therapeutics, University at Albany, Albany NY
• Introduction to Newborn Screening: How and Why Now? Andy Rohrwasser, PhD, MBA, Chief Scientific Officer, Myotonic Dystrophy Foundation, Oakland, CA
• Introduction to Congenital Myotonic Dystrophy, Nicholas Johnson, MD, MSc, FAAN, Professor, Director of the Center for Inherited Muscle Research, Virginia Commonwealth University, Richmond, VA
• NICU Sequencing: Ultrafast Solution: Scientific Evidence, Economic Sense, Stephen Kingsmore, MD, DSc; President/CEO of Rady Children’s Institute for Genomic Medicine, San Diego, CA
• Pilot Study: Towards Population Wide Sequencing; Wendy Chung, MD, PhD; Chief of Pediatrics, Boston Children’s Hospital, Professor, Harvard Medical School, Boston MA
• Newborn Sequencing in Public Health: How would it work in NY? Michele Caggana, ScD, FACMG; Deputy Director, Division of Genetics; Director, Newborn Screening Program; Department of Health, Wadsworth Center, Albany NY
• Rapid Advance in Analysis and Interpretation; Opportunities in EHR mining - before population wide screening? Mark Yandell, PhD; Professor, Director Eccles Institute Bioinformatics Program; Technical Director, Utah Genome Project; The University of Utah, Salt Lake City, UT

Key Meeting Outcomes and Insights

Following general presentations to the public and interested scientific community members at the University at Albany, the key stakeholders held an in-person discussion with a few virtual attendees. Several important outcomes and insights emerged from the discussion. The Guardian Study was highlighted, as a large-scale genomic screening initiative in New York City, which has screened over 15,000 participants to date and reported a 3.3% positive screen rate with an average turnaround time of approximately 22 days.

Whole genome sequencing (WGS) in neonatal intensive care units (NICUs) was highlighted as the ultimate promise in the ultra-rapid diagnosis reducing time-to-diagnosis and eliminating diagnostic odysseys, but also reducing pain and suffering based on misdiagnoses and associated unnecessary diseases management, while also significantly reducing healthcare costs. The stakeholders also highlighted that repeat expansion disease testing is gaining attention, particularly for conditions such as congenital myotonic dystrophy.

While support for the need for increased testing was strong amongst the group, significant policy and infrastructure challenges were noted. Many states currently lack formal policies for reimbursement for WGS diagnostics, posing a significant fiscal challenge to NBS screening programs. While New York State has pilot programs, there is no statewide policy in place for the selection of disease candidates. Sequencing costs, estimated at around $60 per newborn, along with the need for equipment redundancy and trained personnel, were also raised as significant logistical barriers. The rigorous nature of the Recommended Uniform (newborn Screening) Panel (RUSP) nomination process, which involves a nine-month review process and a 120-day decision window requiring strong evidence of treatment efficacy and public health impact would be significant challenges at this time. This is further complicated by the current administration’s dissolution of the Secretary’s Advisory Committee for Heritable Disorders in Newborns and Children that halted the process and disrupted the mechanism for adding or removing disorders from the recommended panel.

The need for an effective treatment for newborns with DM was discussed as an important point needed to support NBS. Given that clinical trials are currently primarily focused on adults, it was noted that the timeline for approved treatments for newborns was unclear. Foundational to this lack of treatment however is long-term natural history and outcome data for children affected by the early onset form of DM.

Ethical and social considerations were also discussed by the group. Concerns were raised about the implications of screening for conditions without available treatments, including the significant psychological impacts to the affected families and issues associated with insurance and insurability. Clinicians and patient advocates raised the point that early diagnosis can significantly affect family planning and emotional well-being of DM families. There was universal recognition of need for further real-world data and comprehensive, long-term natural history studies, given that many symptomatic individuals remain undiagnosed.

Recommended Next Steps

Several next steps were recommended by the group to advance the field. In terms of research and data collection, more long-term natural history and outcome studies were recognized as essential to understand disease progression and optimal treatment timing. The latter was a key highlight for myotonic dystrophy type 1 (DM1), which is highly heterogeneous in presentation between affected individuals. Integrating real-world data and study data, exploring genotype-phenotype relationships through collaborations with organizations like MDF and academic networks were also raised as crucial next steps. Pilot studies, utilizing EHR mining identifying undiagnosed DM patients for example in the Intermountain Health system, could help assess the feasibility and outcomes of broader implementation and bridge towards the implementation of newborn screening.

From a policy and advocacy perspective, gaining provider buy-in is critical. Here, for example RTI-led focus groups and precedence from other diseases were identified to potentially help to identify provider perspectives and barriers as well as preparing comprehensive evidence packages for RUSP nominations, including cost-benefit analyses and patient impact data. While the likelihood of NBS screening for DM1 was recognized as being years away from reality, the potential of maternal screening initiatives for DM, potentially in partnership with professional organizations like American College of Obstetricians and Gynecologists (ACOG), American College of Medical Genetics and Genomics (ACMG) or Society for Maternal-Fetal Medicine (SMFM) and commercial reference laboratories through integration in existing maternal panels was recognized.

Community engagement was identified as a key focus area raised by the experts and stakeholders alike. The collective group believed that targeted educational materials should be developed to inform families about the opportunities, implications and options related to genetic testing. The involvement of a broad coalition of stakeholders, including families, advocacy groups, and clinicians, was felt to be essential to align priorities and address ethical considerations. The group also believed that current efforts should include ensuring equitable access to testing and support systems for newly diagnosed families.

In summary, while the implementation of NBS for DM faces significant logistics and regulatory hurdles given the lack of an approved treatment approach for newborns affected by the disease, there was recognition of the power, opportunity and necessity of screening and diagnostic sequencing to make an impact on the DM community.

A recent publication in Nature Genetics explores base editing as a solution to repeat expansion diseases similar to myotonic dystrophy (DM). The summary below was created by Asmer Aliyeva, PhD Candidate in Dr. Andy Berglund’s lab at the RNA Institute, in collaboration with MDF's Chief Scientific Officer, Dr. Andy Rohrwasser, who aims to work with graduate and undergraduate students to share groundbreaking scientific discoveries with lay audiences.

Some diseases that affect the brain, muscles, and nerves are caused by tiny pieces of DNA that repeat too many times. These repeated sections can cause serious problems when they get too long. Diseases like Huntington’s, Friedreich’s ataxia, and myotonic dystrophy are caused this way.

• Huntington’s happens when there are too many CAG repeats in the HTT gene.
• Friedreich’s ataxia is caused by too many GAA repeats in the FXN gene.
• Myotonic dystrophy type 1 (DM1) is caused by too many CTG repeats in the DMPK gene.
• Myotonic dystrophy type 2 (DM2) is caused by too many CCTG repeats in the CNBP gene.

As repeats grow longer over time or through generations, they make the disease worse.

A New Way to Help: Base Editing

Scientists found that breaking up these long repeats with different DNA letters can make the disease start later or be less severe. A research team at Harvard tested if they could do this using a tool called base editing. Think of DNA like a book written with the letters A, T, C, and G. Base editing works like an eraser-pencil combination that can fix one wrong letter without tearing the entire page or making the sentence unreadable. The editing tool finds the right letter and carefully changes it.

The scientists used this method on cells and mice with Huntington’s and Friedreich’s ataxia. It stopped the repeats from growing and sometimes even made them shorter. In mice, it even helped reduce repeat growth in the brain. But sometimes the tool changes the wrong part of DNA, so scientists are working to make this eraser-pencil tool safer.

What About Myotonic Dystrophy?

Myotonic Dystrophy (DM) is caused by extra repeats—CTG for DM1 and CCTG for DM2. It can cause muscle weakness, trouble relaxing muscles, heart issues, and more. Like the other diseases, the more repeats there are, the worse it gets. This study gives hope that base editing might help people with DM, too. If it works safely, it could slow down the disease, reduce symptoms, and lead to better treatments in the future.

Why It Matters

Base editing is a new and precise way to fix small DNA mistakes. It’s still being tested, but it could bring better treatments for diseases like Huntington’s, Friedreich’s ataxia, and Myotonic Dystrophy. Click here to learn more about base editing!

Original Publication: 

Matuszek, Z., Arbab, M., Kesavan, M. et al. Base editing of trinucleotide repeats that cause Huntington’s disease and Friedreich’s ataxia reduces somatic repeat expansions in patient cells and in mice. Nat Genet (2025). https://doi.org/10.1038/s41588-025-02172-8

Meet one of our 2025 Pilot Grant Recipients, Stéphanie Tomé, PhD! Dr. Stéphanie Tomé, a researcher at the Myology Institute in Paris, has over 15 years of experience. Her research has focused on trinucleotide repeat instability in various neurological and neuromuscular disorders, including Huntington’s disease and myotonic dystrophies. Her current work centers on DM1 and the mechanisms underlying CTG repeat instability. More recently, she has expanded her expertise to DM2.

Within her team, Dr. Tomé has played a key role in developing and implementing long-read sequencing (LRS) methods specifically tailored for analyzing repetitive sequences. Her work has involved close collaborations with leading sequencing companies, including Pacific Biosciences and Oxford Nanopore, as well as the platforms at the Curie Institute. These efforts have established her as a specialist in LRS for the study of repeat expansion and repeat instability. In 2024, she organized the 2nd Long-Read Sequencing of Expanded Tandem Repeats Workshop, held in Paris, bringing together experts from Europe and North America to exchange knowledge and review the latest advances in repeat-associated disease research. 

Dr. Tomé is an active member of an international research group studying disorders associated with unstable tandem repeats, further demonstrating her long-term commitment to advancing the field. Her ultimate goal is to improve healthcare for DM patients and contribute to the development of innovative therapeutic strategies through collaborative, multidisciplinary research efforts.

Click here to learn more about MDF's research funding opportunities and prior grant recipients.