Sequencing EBS genes (2025)

We are deeply grateful to DEBRA UK, not only for the funding but for believing in the importance of research in underrepresented regions. Thank you for making this work possible, and for helping us give a voice—and answers—to EB families in Argentina.

Researchers studied the DNA from 180 people who appeared to have EBS and identified the specific genetic cause for 161 of them. 114 people had genetic changes in genes for keratin (EBS). Researchers found 27 different genetic changes in the gene for keratin-5, 10 of which had never been reported before.

44 of these patients had a specific change (called KRT5:c.1649del) and had been diagnosed with EBS with mottled pigmentation (dark spots on the skin) or EBS with migratory circinate erythema (ring-shaped red patches). The genetic work showed that these two subtypes with different names are actually caused by the same genetic change.

A minority of patients didn’t appear to have genetic changes in the genes for keratin-5 or keratin-14 so the researchers checked other genes associated with EB. 17 people were found to have a genetic change in the gene for collagen-7 so were diagnosed with dystrophic EB (DEB). Another 11 people had either junctional EB (JEB), Kindler EB (KEB) or EBS caused by changes to other genes.

No clear genetic cause was found for 19 of the 180 people with EBS-like symptoms.

Researchers have taken the first steps toward creating a national registry of EB patients in Argentina, allowing them to get an idea of how many people in Argentina are affected by EB for the first time.

They published their work describing how many people are affected by EB in a poster at the World Congress of Pediatric Dermatology in April 2025, and a poster at the 2024 Congreso Argentino de Dermatologia. 

2024 video update:

Lead researcher: Dr Laura Valinotto is a researcher at Argentina’s National Scientific and Technical Research Council and a principal investigator (PI) at CEDIGEA. She holds an MSc in Biotechnology from the School of Biochemistry and Pharmacy at the National University of Rosario, Argentina and obtained her PhD degree at the School of Biochemistry and Pharmacy at the University of Buenos Aires, with her work on molecular epidemiology of respiratory paediatric viral infections at the Virology Lab in the Children’s Hospital R. Gutiérrez. While completing her PhD, she started to volunteer with the Dermatology Department of the hospital in order to find a way to diagnose genodermatosis patients attending the children’s public hospital. After some years, she was one of the founders of the Centre for Research in Genodermatosis and Epidermolysis Bullosa (CEDIGEA), at the University of Buenos Aires (UBA). Here she continues her work on molecular diagnosis of genodermatoses, together with epidemiological molecular research of the population in order to develop algorithms to perform cost-effective diagnosis of low-income patients and build detailed clinical and molecular records of EB to better understand the pathogenesis of the disease.

Co-researchers: Prof Graciela Manzur is Professor and Head of the Department of Dermatology at the School of Medicine, University of Buenos Aires. She is a neonatologist, paediatrician and dermatologist and worked as a paediatric dermatologist at the R. Gutierrez Children’s Hospital for more than 15 years where she managed to open a new section of Rare Skin Diseases at the Hospital. After some years, and together with a multidisciplinary group, she founded the CEDIGEA, where she is the Director. After seeing so many children with EB grow up, she realised the necessity of a place where adult EB patients could be treated and she launched a second CEDIGEA centre, for adults, at the Hospital de Clínicas at the University of Buenos Aires.

Dr Mónica Natale is a biochemist involved in the molecular diagnosis of genodermatoses at the R Gutiérrez Children’s Hospital. She was also one of the founders of the CEDIGEA and is in charge of the molecular lab, identifying new EB cases and developing new strategies for the diagnosis of other genodermatoses.

“The individual benefit for each of our EB patients is that molecular diagnosis will be available for them to determine the type and subtype of EB and provide an unequivocal diagnosis which is essential to give the best care and genetic counselling. The collective benefit is that the collected information about variants prevalence may be useful in shortening the diagnostic odyssey for future patients… and offer a more accurate prognosis. Additionally, in populations with unexplored genetic background, these studies could reveal a previously unknown diversity of pathogenic variants that should be considered when defining targets for gene therapies.”

– Dr Valinotto

Grant title: Molecular epidemiology of Epidermolysis Bullosa Simplex in Argentina.

One of the main objectives of the Centre for Research in Genodermatoses and Epidermolysis Bullosa (CEDIGEA) in Argentina is to provide all EB patients with an accurate diagnosis in order to better and more effectively address the symptoms they suffer from, manage pain, and provide the interdisciplinary care they need, regardless of their social condition. Our goal in this project is to characterize our patients clinically and molecularly since there are not many reports from EB in South America. At CEDIGEA, we have had the opportunity to publish a similar study with DEB and Kindler patients, and our goal is to complete and publish the study of EBS patients.

Our Centre for Research in Genodermatoses and Epidermolysis Bullosa (CEDIGEA) at the University of Buenos Aires diagnoses and follows up patients without health insurance in Argentina. The aim of this project is to discover the prevalence and diversity of genetic variants associated to EBS in our population, which has an unexplored background. Being able to report if novel variants are found in our region and building a database determine if new phenotypegenotype associations can be inferred is of utmost importance. This research project will, at the same time, allow us to offer our low-income patients a definitive molecular diagnosis free of charge.

With the help of the Buenos Aires Faculty and the efforts of CEDIGEA professionals, we had the opportunity to successfully carry out a previous project involving patients with DEB, where we diagnosed 181 patients from 136 unrelated families, finding 36 novel variants and a new phenotype-genotype association.

Understanding Epidermolysis Bullosa Simplex in Argentina: What We Discovered and Why It Matters

This project was born from a clear need: to better understand Epidermolysis Bullosa Simplex (EBS) in people from Argentina, a group that has been underrepresented in EB research. Thanks to funding from DEBRA UK, we were able to carry out a study that not only deepened our knowledge of this disease, but also gave families long-awaited answers.

 Our work focused on the clinical and genetic analysis of people who had been diagnosed or suspected to have EBS. We studied more than 180 individuals from 121 families who came to our center (CEDIGEA, based at the University of Buenos Aires) with symptoms suggesting EBS or another type of EB. Most of these families live in vulnerable conditions and have little or no access to specialized care.

To identify the genetic cause of their condition, we started by analyzing key regions (called “exons”) of two genes known to be involved in EBS: KRT5 and KRT14. Based on our earlier findings in local patients, we focused first on exons 1 and 9 of KRT5 and exons 1 and 6 of KRT14. This strategy proved very effective and affordable. By May 2024, we had found the genetic cause for 104 patients from 59 families.

We then extended our analysis to other parts of the same genes and found 10 more genetic changes affecting 29 patients. As more families continued to arrive, we diagnosed nine additional individuals. In total, we discovered 27 different variants in the KRT5 gene, 10 of which had never been reported before. One variant in particular—called KRT5:c.1649del— stood out. It was found in 44 people from 16 unrelated families and had previously been reported in only 11 families worldwide.

When we looked more closely at these 44 patients, we noticed something remarkable: although some had been diagnosed with EBS with mottled pigmentation (dark spots on the skin), others had ring-shaped red patches (a type known as EBS-MCE). We realized that these were not two different subtypes but part of the same disease spectrum. In other words, the symptoms may change over time, but the underlying cause is the same. Recognizing this helps doctors give better advice and anticipate how the disease might evolve.

We summarized these findings in a scientific article titled “Epidermolysis Bullosa Simplex with Mottled Pigmentation and Migratory Circinate Erythema: Distinct Subtypes or a Continuum?”, which we submitted to an specialized journal. This is the first in a series of three articles we plan to publish with results from this project.

Not all patients had EBS. For those still undiagnosed after the first round of tests, we sequenced other genes, especially COL7A1, which is linked to Dystrophic EB (DEB). This strategy led to 17 more diagnoses. For the remaining 30 patients, we used advanced sequencing techniques that allowed us to examine many genes at once. We diagnosed another 11 patients with a mix of EB types, including Junctional EB, Kindler EB, and EBS caused by rarer genes like PLEC and KLHL24. In the end, we found a clear genetic answer for 161 of the 180 patients.

This work has enormous meaning for families. Receiving a definitive diagnosis not only ends the uncertainty but also opens doors to better care, genetic counseling, and, eventually, access to treatments or clinical trials.

Why this work matters

One of the most surprising findings was just how common the KRT5:c.1649del variant was in our population, compared to its rarity elsewhere. This highlights the importance of studying EB in different parts of the world. If research is only done in Europe or North America, we miss key pieces of the puzzle.

We were also able to reconstruct how this disease variant likely spread through families in a specific region of northeastern Argentina. This finding confirms the idea of a founder mutation, passed down from a shared ancestor. Understanding these patterns can help guide future screening and diagnosis in the region.

Beyond the science, this project had a broader impact. Having the support of DEBRA UK gave visibility to our work and encouraged more physicians across Argentina and neighboring countries to refer patients to us. As a result, we took the first steps toward creating a national registry of EB patients in Argentina, collecting data from the four main centers caring for people with EB. This allowed us to make a preliminary estimate of how common EB is in our country—something that had never been done before.

Overcoming challenges

Despite the success, the path was not easy. Argentina is going through one of the worst economic crises in its history. We faced serious delays importing reagents, dealing with inflation, and adapting to changing costs. At one point, we had to completely revise our original plan, since we couldn’t buy the reagents we had hoped for. Still, thanks to the six-month extension granted by DEBRA UK, and a shift in strategy, we managed to meet all our objectives.

What’s next?

We are now working on two additional scientific papers from this project. We also continue to follow up with patients and are working to share our findings with local dermatologists and pediatricians to improve early diagnosis across the country. The registry we started will be a key tool for planning public health policies, providing better support to families, and—hopefully— bringing us one step closer to accessible treatments. (From 2025 final report.)

We are deeply grateful to DEBRA UK, not only for the funding but for believing in the importance of research in underrepresented regions. Thank you for making this work possible, and for helping us give a voice—and answers—to EB families in Argentina.

(From June 2025 final report.)

We’ve made significant progress in our project at the Centre for Research in Genodermatosis and Epidermolysis Bullosa (CEDIGEA). Currently, we’ve recruited 180 patients from 121 families who were referred to us due to clinical suspicion of Epidermolysis Bullosa Simplex (EBS) or other Epidermolysis Bullosa of undefined type.

Our main goal was to perform genetic analysis to provide molecular diagnoses, and at the same time to learn about the genetic basis of the disease in our population. So far, we’ve analysed specific genes and achieved a molecular diagnosis for 104 patients, which is a substantial accomplishment. In doing so, we’ve identified 31 different pathogenic variants, with 12 of them being previously unreported in the literature.

However, challenges arose during our project. We encountered delays in acquiring necessary reagents for genetic sequencing due to economic instability and changing regulations in our country, with the prices of the laboratory supplies being 300% higher than three years ago. Due to these challenges, we’ve had to revise our strategy to make the most of our grant funds and ensure timely completion of our objectives.

Regarding publications, we’re preparing a comprehensive manuscript to present our findings. We believe that by studying such a large number of cases, we will be able to detect particularities in each patient and groups of patients, and this data will be useful to predict how the disease will develop in future patients.

As for patient involvement, Magdalena and Josefina have been instrumental. Through their blog “En mi piel”, they’ve provided valuable insights and created a platform for patients to share their experiences. This patient-centred approach guides our research focus and ensures that our work addresses the needs of those affected by Epidermolysis Bullosa and other rare skin diseases.

In summary, despite the challenges, our project is progressing well, and we’re committed to advancing research in the field of Epidermolysis Bullosa for the benefit of patients worldwide.

And we don’t want to miss this opportunity to invite you to the V Argentine Congress of Genodermatoses and Epidermolysis Bullosa, in virtual format, on September 19th, 20th, and 21st, 2024. To stay updated, follow us on our Instagram @cedigea.uba

(From May 2024 progress report.)