A genetic disease is a health condition caused by an alteration in an individual’s deoxyribonucleic acid (DNA) sequence or structure. DNA acts as the instruction manual for the body, and any significant error in this manual can disrupt the normal function of cells, tissues, and organs. These alterations, often called mutations or variants, can range from a single misplaced chemical building block to the gain or loss of an entire chromosome. Understanding the cause involves determining the scale of the DNA error and the specific mechanism by which it leads to a disease state.
Errors Originating in a Single Gene
The most straightforward type of genetic disease results from a malfunction within a single, specific gene, often referred to as Mendelian disorders. These conditions are caused by small changes in the gene’s DNA sequence, such as a point mutation, which is like a single-letter typo. This miscoding can lead to the production of a faulty protein, a protein that works inefficiently, or no protein at all.
These single-gene disorders typically follow predictable inheritance patterns. In Autosomal Recessive disorders, such as Cystic Fibrosis, a person must inherit two copies of the altered gene—one from each parent—to develop the disease. The parents themselves are usually unaffected carriers because their single healthy copy of the gene compensates for the faulty one.
By contrast, Autosomal Dominant disorders require only one copy of the altered gene for the disease to manifest. For example, in Huntington’s Disease, inheriting just one mutated copy of the HTT gene is sufficient to cause the neurodegenerative condition. The mutated gene often produces a toxic or malfunctioning protein that overrides the function of the protein produced by the healthy copy. These disorders tend to appear in every generation of an affected family.
Large-Scale Chromosomal Changes
This category of genetic disease involves large-scale changes to the structure or number of chromosomes, which are the tightly packed bundles of DNA. These errors affect hundreds or thousands of genes simultaneously. The incorrect dosage of genes, either too many or too few, overwhelms the body’s normal developmental processes.
A common mechanism for this type of error is called nondisjunction, the failure of chromosomes to separate properly during the formation of egg or sperm cells. This mistake leads to a gamete with an abnormal number of chromosomes, known as aneuploidy. The most frequently cited example is Trisomy 21, or Down Syndrome, where an individual inherits three copies of chromosome 21 instead of the usual two.
Structural abnormalities can also occur, where parts of chromosomes are rearranged. These include large deletions, where a segment of a chromosome is missing, or duplications, where a segment is repeated. Translocations involve segments of two different chromosomes swapping places, which can lead to a disease if the rearrangement disrupts a gene or results in an unbalanced transfer of genetic material.
Complex Interactions of Genes and Environment
The majority of common diseases, including heart disease, type 2 diabetes, and most cancers, are not caused by a single gene or a single chromosomal error. They result from a complex interplay of many factors. These are known as multifactorial or polygenic diseases, meaning they involve multiple genes. Each individual gene contributes only a small amount of risk, which is why these conditions do not follow the simple inheritance patterns seen in single-gene disorders.
The concept of genetic predisposition is central to this category. An individual inherits a set of genetic variations that increase their susceptibility to developing a disease. This genetic susceptibility is typically not sufficient to cause the disease on its own. The disease only manifests when a threshold is crossed due to external triggers.
Environmental factors, which include diet, lifestyle choices like smoking, physical activity, and exposure to chemical agents, act as the triggers. For instance, a person may have a polygenic risk score indicating a high genetic susceptibility for type 2 diabetes, but they may never develop the condition if they maintain a healthy diet and active lifestyle. The disease results from a synergy when the inherited genetic risk meets a disease-conducive environment.
Inherited Versus Acquired Genetic Changes
The final distinction in the cause of a genetic disease relates to the timing and location of the genetic change in the body. Genetic alterations are categorized as either germline or somatic, determining whether the condition can be passed down to the next generation.
Germline mutations are present in the reproductive cells—the egg or sperm—and are passed from a parent to their offspring. If a child inherits a germline mutation, every cell in their body will carry that genetic alteration from conception onward. All the single-gene disorders and most chromosomal changes discussed previously are examples of germline mutations because they are present at birth.
Somatic mutations, by contrast, occur in body cells (soma) after conception and are not present in the reproductive cells. These changes are acquired during a person’s lifetime due to errors in DNA replication or exposure to environmental mutagens like UV radiation or tobacco smoke. Somatic mutations are localized to specific cells or tissues and cannot be passed to a person’s children. For example, the vast majority of cancers are caused by the accumulation of somatic mutations in a specific tissue, leading to uncontrolled cell growth and division.