The genetic landscape of muscle diseases is significantly more complex than initially anticipated.
In the so-called Mendelian inheritance, genetic diseases are caused by DNA changes (mutations) in a single gene that lead to a molecular, cellular, or tissue defect, producing a predictable disease phenotype (one gene–one disease).
Beyond the “One Gene – One Disease” model
While traditional Mendelian inheritance patterns explain many neuromuscular conditions, the “one gene–one disease” model increasingly fails to explain the full spectrum of clinical presentations.
In muscle diseases such as distal myopathies, myofibrillar myopathies, limb-girdle muscular dystrophies (LGMD), and congenital myopathies, patients often present with atypical clinical presentations (phenotypes), even among family members carrying the same pathogenic variant (phenotypic variability). Furthermore, many patients with clinical features consistent with myopathy do not have identifiable mutations in known disease-associated genes.
While some of these cases may be due to mutations in yet-to-be-discovered genes, recent findings suggest that a disease may also originate from the co-existence of small changes in different genes (multilocus inheritance models).
DNA is like a recipe passed down through a family—similar to how cousins might share a version of the same dish, DNA codes in different organisms can have slight variations but still produce similar outcomes. However, just as a small change in a recipe—like forgetting an ingredient—can ruin a dish, even a tiny change in the DNA code can disrupt how the body functions and lead to disease.
In some cases, known as digenic inheritance, two separate recipes each have a small change that wouldn’t matter on their own, but when combined, they ruin the final meal—similarly, changes in two different genes together, encoding for proteins that are structurally or functionally related, can cause a disease. If you only have one of these changes, you won’t get sick from it. It’s the combination that causes the disease.
Let’s look at some examples in muscle diseases.
Welander-like distal myopathy is a muscle weakness that appears later in life. Researchers found that people with this condition have a specific change in two genes: SQSTM1, that is usually known for its role in other diseases like Paget’s disease (a bone condition) and ALS (a nerve disease), and TIA1, that helps process the instructions our cells need to build proteins. Neither change alone causes muscle disease, but when someone has both, they develop a myopathy.
More recently, other muscle diseases have been linked to changes in two different genes: TTN, the gene that encodes for titin, a huge protein that is super important for the structure and function of our muscles, including our heart, and SRPK3. This gene helps with a process called “splicing,” which is how our body fine-tunes the instructions from our genes. Again, it’s the combination of changes in both TTN and SRPK3 that’s now being looked at as a cause for certain muscle problems.
The future of complexity understandingThe genetic architecture of muscle diseases is increasingly recognized as complex, multilayered, and dynamic. Digenic inheritance represents just one example of how multiple variants can interact to produce disease, highlighting the limitations of the traditional “one gene–one disease” model.
These examples show us that sometimes, understanding a disease isn’t as simple as finding one mutated gene. Instead, it can be a “two-hit” scenario where the right (or wrong!) combination of genetic changes is what ultimately leads to the disease.
AI-based initiatives, such as CoMPaSS-NMD, will further unravel this complexity by identifying how combinations of genetic variants contribute to specific neuromuscular phenotypes.
