What is this rash? DNA fingerprinting can help doctors more effectively diagnose and treat skin conditions

Rashes can be thought of as a dysfunctional community of skin cells. Your skin is home to dozens of distinct cell types, including those that form blood vessels, nerves, and the skin’s local immune system. For decades, clinicians have largely diagnosed rashes with the naked eye. Although examining the physical appearance of a skin sample under a microscope can work for more obvious skin conditions, many rashes can be difficult to tell apart from one another.

At the molecular level, however, the differences between rashes become clearer.

Scientists have long known that molecular abnormalities in skin cells cause the redness and flaking seen in conditions such as psoriasis and eczema. While almost every different type of cell in your skin can release chemicals that make inflammation worse, which ones lead to the formation of rashes remains a mystery and can vary from patient to patient.

But molecular testing of rashes is not common practice due to technological limitations. Using a new approach, my colleagues and I were able to analyze the genetic profiles of skin rashes and quantitatively diagnose their root causes.

The skin is a complex organ that performs a wide variety of functions.

High resolution skin profiles

Traditional genetic analyzes work by averaging the activity of thousands of genes across millions of cells.

Genetic testing of tissue samples is common practice for diseases such as cancer. Clinicians collect and analyze tumor biopsies from patients to determine the unique molecular characteristics of a particular cancer. This genetic fingerprint helps oncologists predict whether a cancer will spread or what treatments might be most effective. Cancer cells lend themselves to this form of testing because they often grow into recognizable masses that make them easy to isolate and analyze.

But the skin is a complex mixture of cells. Grouping these unique cellular communities into a single group can obscure genetic signatures essential for diagnosis.

Recent technological advances called single-cell RNA sequencing, however, have allowed scientists to preserve the identity of each type of cell that lives in the skin. Instead of averaging the genetic signatures of all cell types in bulk, single-cell RNA sequencing analyzes allow each cell to retain its unique characteristics.

Single cell RNA sequencing is used to analyze samples where many different cell types are present.

Using this approach, my colleagues and I isolated over 158,000 immune cells from skin samples from 31 patients. We measured the activity of approximately 1,000 genes from each of these cells to create detailed molecular fingerprints for each patient. By analyzing these fingerprints, we were able to identify genetic abnormalities unique to the immune cells residing in each type of rash. This allowed us to quantitatively diagnose otherwise visually ambiguous rashes.

We also observed that some patients had treatment responses consistent with what we expected with our predicted diagnoses. This suggests that our concept could be viably extended for further testing.

This diagram shows that the genetic fingerprint (colored in red and yellow) of eczema (AD, or atopic dermatitis) is stronger than that of psoriasis (PV).
Reprinted with permission from Yale Liu et al., Science Immunology 7:eabl9165 (2022)

To make our approach available to clinicians and scientists, we have developed an open-source web database called RashX that contains the genetic fingerprints of different skin rashes. This database will allow clinicians to compare the genetic profile of their patients’ rashes to similar profiles in our database. A closely matching genetic fingerprint could provide clues to the cause of their patient’s rash and lead to potential treatment pathways.

Open-source diagnostics

The rapid development of drugs targeting the immune system in recent years has inundated doctors with difficult treatment decisions for individual patients. For example, while some drugs that act on the immune system are known to work well for conditions like psoriasis or eczema, many patients have atypical skin rashes that cannot be accurately diagnosed.

An open-source database like ours could allow clinicians to profile and diagnose these rashes, providing a springboard for choosing an appropriate treatment.

Additionally, chronic inflammatory diseases that affect organs other than the skin share similar genetic abnormalities. Laboratory tests that can shed light on the root causes of skin diseases can probably be extended to many other conditions.

Our RashX project initially focused on two very common types of rashes, psoriasis and eczema. It’s unclear whether other types of rashes will have similar genetic profiles to psoriasis and eczema or instead have their own unique fingerprints. It is also unclear which parts of the fingerprint would best predict response to the drug.

But RashX is a living web resource that will become more useful as more scientists collaborate and contribute new data. Our lab is also working to simplify the process of developing rash genetic profiles to make participation in this area of ​​research more accessible for clinics around the world. With more data, we believe projects like RashX will make precision testing for rashes a critical next step in diagnosis and treatment.

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