While many conditions trace back to a single gene, some traits and disorders require multiple genetic factors. Digenic inheritance is a specific mechanism where a medical condition only appears when pathogenic variants, or mutations, are present in two different genes simultaneously. This pattern is a departure from more straightforward inheritance where a single altered gene is responsible for a condition. A disruptive variant in just one of the two associated genes is not enough to cause disease, as the other gene can often compensate. The condition manifests only when both genes are compromised.
Genetic Inheritance: Beyond Single Genes
Genes are segments of DNA that provide the blueprint for molecules the body needs to function. A mutation is a change in a gene’s DNA sequence that can alter the function of the protein it codes for. In many genetic disorders, the inheritance pattern is monogenic, meaning a mutation in just one gene is sufficient to cause the disease.
Monogenic disorders include conditions like cystic fibrosis, which requires inheriting two mutated copies of a gene. Another form is autosomal dominant inheritance, seen in conditions like Huntington’s disease, where inheriting just one copy of the mutated gene is enough to cause the disorder. This “one gene, one disease” model has been foundational to medical genetics.
Advancements in genetic analysis show that many conditions are more complex. The expression of certain phenotypes, or observable traits, cannot be explained by a single gene mutation alone. This has led to the recognition of patterns where interactions between multiple genes are necessary for a condition to develop. Digenic inheritance is the simplest form of multi-gene interaction, acting as a bridge between monogenic and complex multifactorial diseases.
How Digenic Inheritance Works
For a digenic condition to emerge, the two involved genes are often functionally related. This means their protein products may interact directly or participate in the same biological pathway. The interaction creates a system with built-in redundancy; if one component is faulty, the other can often maintain sufficient function.
A person who inherits a mutation in only one of the two genes is a carrier and may show no symptoms. The unaltered partner gene provides enough functional protein to prevent the disease through a process known as compensation. The disease state is only reached when a functional threshold is crossed, which requires both genes to be compromised. This combined effect disrupts the biological pathway to a degree that neither mutation could achieve alone.
The requirement for two simultaneous genetic “hits” explains why some genetic conditions show reduced penetrance, where individuals carrying a known disease-associated mutation do not develop the disorder. In some of these instances, the missing piece is a second, undiscovered mutation in an interacting gene.
Exploring Different Digenic Scenarios
Digenic inheritance is not a single process but a category with several interaction models. The most straightforward is “true” digenic inheritance, where mutations in both genes are required to produce the disease phenotype. An individual with a pathogenic variant in only one of the two genes will be completely unaffected, as will a person with a variant in the other. The condition only appears when an individual inherits one mutation from each of the two different genes.
A different model is “composite” digenicity, which involves a gene-modifying effect. In this scenario, a primary mutation in one gene is the main driver of the disease and may cause a mild or incomplete form of the condition on its own. When a second mutation is inherited in a different, modifying gene, it exacerbates the clinical picture, leading to a more severe disease phenotype. The second gene acts to worsen the effects of the first.
A third situation can arise from the co-inheritance of two mutations that are each known to cause a distinct monogenic disease. When inherited together, they can result in a new, blended, or more severe phenotype that is different from either of the individual disorders. This scenario, sometimes called a “dual diagnosis,” results from the combined impact of two separate conditions. This is distinct from true digenic inheritance, which involves two genes interacting to cause a single, specific condition.
Digenic Conditions and Their Implications
Several human diseases follow a digenic inheritance pattern. The first well-documented example was a form of retinitis pigmentosa, a degenerative eye disease. The disease only manifests in individuals with mutations in both the PRPH2 and ROM1 genes. These genes produce proteins that interact to form structures in the eye’s photoreceptor cells, providing a clear biological basis for their relationship.
Another condition with digenic aspects is Bardet-Biedl syndrome, which affects multiple body systems. Some forms of genetic haemochromatosis, an iron overload disorder, also show digenic inheritance. While most cases are linked to the HFE gene, some individuals have more severe disease by inheriting an HFE mutation along with a mutation in another iron-regulating gene like HJV or TFR2.
Digenic inheritance has significant consequences for genetic testing and counseling. Identifying these conditions requires analyzing multiple genes at once, often using next-generation sequencing (NGS). Finding two variants complicates diagnosis, as it can be difficult to prove both contribute to the disease and are not co-occurring by chance. Genetic counseling is also more complex, as the risk of passing the condition to offspring does not follow simple ratios and requires explaining the combined probabilities of inheriting both mutations.