Rare diseases are medical conditions that affect a small percentage of the population. In the U.S., a disease is classified as rare if it affects fewer than 200,000 people, while in Europe, it is considered rare if fewer than 1 in 2,000 people are affected. Despite their individual rarity, these conditions collectively impact millions of people worldwide, with over 7,000 identified rare diseases. Genetic testing helps identify their underlying causes.
Understanding Genetic Testing for Rare Diseases
Genetic testing analyzes an individual’s DNA to identify variations or mutations linked to a particular disease or condition. Its purpose for rare diseases is to diagnose or confirm suspected conditions by pinpointing specific genetic causes. Since approximately 80% of rare diseases have a genetic origin, these tests have significantly advanced the diagnostic process.
An accurate diagnosis of a rare disease can significantly improve a patient’s quality of life and overall prognosis. Many individuals with rare diseases face a lengthy diagnostic journey, often referred to as the “diagnostic odyssey,” which can last for years and involve seeing numerous specialists. Genetic testing can substantially reduce this time by providing precise information about the underlying genetic cause, allowing for earlier intervention and personalized treatment plans. This can also provide emotional relief for patients and their families by ending years of uncertainty.
Methods of Genetic Testing
Several types of genetic tests are used for rare diseases, varying in scope and the amount of DNA analyzed. Single-gene testing looks for changes in one specific gene, often chosen when a particular condition with a known genetic mutation is suspected in a family. For instance, if Huntington’s disease is suspected, testing would focus on the HTT gene.
Gene panels analyze multiple genes simultaneously, typically a group of genes associated with a particular set of symptoms or a specific disease category. This method is useful when a condition could be caused by mutations in any of several genes, such as certain forms of muscular dystrophy or epilepsy. While more comprehensive than single-gene testing, panels are still focused on known disease genes.
More extensive tests include exome sequencing (ES) and genome sequencing (GS), which utilize next-generation sequencing (NGS) technology. Exome sequencing focuses on the exons, the protein-coding parts of genes, which constitute about 1% of the genome but contain approximately 85% of known disease-causing mutations. Genome sequencing analyzes a person’s entire genome, offering the most comprehensive look at genetic information, including both protein-coding and non-coding regions. These broader tests are often employed when single-gene or panel testing has not yielded a diagnosis, or when the suspected condition’s genetic cause is unclear, providing a higher diagnostic yield.
The Genetic Testing Journey
The process of pursuing genetic testing for a rare disease begins with an initial consultation with a healthcare provider, often a genetic counselor or a specialist. This consultation helps determine the most appropriate test based on the individual’s symptoms and family history, and provides an opportunity to discuss what can be learned from the test and the potential implications of different results. Genetic counseling is an important step both before and after testing.
Following the consultation, a biological sample is collected for analysis. This is usually a blood or saliva sample, making the process minimally invasive. The sample is then sent to a specialized laboratory for analysis, where the genetic material is examined for changes or mutations associated with rare diseases. Advanced bioinformatics tools identify specific genetic markers from the vast amount of data generated.
The time frame for receiving results can vary, but some whole genome tests can deliver results in approximately two weeks. Once the analysis is complete, the results are sent back to the healthcare provider who ordered the test. The genetic counselor then explains these results to the patient and their family, ensuring they understand the findings and their potential impact.
Interpreting Genetic Test Results
Once genetic test results are available, they are typically classified into three main categories: positive, negative, or a variant of uncertain significance (VUS). A positive result indicates that a gene change, or pathogenic variant, known to cause a disease, has been identified. This confirms a clinical diagnosis or suspicion and can guide treatment decisions, sometimes leading to personalized medicine approaches.
A negative result means that no gene changes known to cause a disease were found in the genes included in the test panel. While often reassuring, a negative result does not always completely rule out a genetic condition, as there may be undiscovered genes or variants not yet included in current tests. If a genetic mutation has already been identified in a family, a negative result for a family member can be considered a “true negative,” indicating they do not have the increased risk associated with that specific familial mutation.
A variant of uncertain significance (VUS) means that a genetic change was found, but there is currently not enough information to determine if it is harmful or benign. VUS results are common, especially when a large number of genes are analyzed. At the time of testing, a VUS typically does not lead to changes in medical care, with clinical decisions continuing to be based on personal and family history. Genetic counseling is particularly important for VUS results to help patients understand the limitations and implications, and in some cases, additional testing of family members may be recommended to help clarify the finding.