Clinical exome sequencing is a genetic test that examines specific parts of an individual’s DNA to identify variations linked to health conditions. It is a significant tool in modern medicine for diagnosing genetic disorders. This method focuses on the most informative sections of the human genome, providing clarity for patients with unexplained medical conditions. The information derived from this testing can guide medical management and provide insights into the underlying causes of disease.
Understanding Clinical Exome Sequencing
The human genome contains all of an individual’s genetic information, organized into long strands of DNA. Within this vast genetic blueprint, segments known as exons carry the instructions for making proteins. These protein-coding regions collectively form what is called the exome. While the exome constitutes only 1% to 2% of the entire genome, it is where about 85% of known disease-causing genetic variations are found.
This targeted analysis allows for efficient identification of genetic changes that may be responsible for a patient’s symptoms. Clinical exome sequencing offers an examination of genes known to be associated with human disorders, including approximately 5,000 disease-causing genes. This method can identify variations in virtually all protein-coding regions, potentially replacing the need for multiple, more targeted genetic tests and improving the chances of finding a diagnosis.
When Clinical Exome Sequencing is Recommended
Clinical exome sequencing is often recommended for individuals with complex, undiagnosed medical conditions that are suspected to have a genetic origin. This includes patients who present with symptoms affecting multiple body systems, or those with suspected genetic disorders where the underlying cause is not immediately clear due to a wide range of possible genetic factors. For instance, developmental delay can be caused by mutations in over 1,000 different genes, making a single, specific genetic test difficult to choose.
The test is also considered when previous, more targeted genetic tests, such as single-gene sequencing or microarray analysis, have not provided a definitive diagnosis. It helps to identify mutations in genes already known to cause disease, and in some cases, can even lead to the discovery of novel genes by comparing exomes from patients with similar features.
The Clinical Exome Sequencing Process
The process of clinical exome sequencing begins with the collection of a biological sample, such as blood or saliva, from the patient. From this sample, high-quality genomic DNA is extracted. Once the DNA is extracted, it is fragmented into smaller pieces.
The next step involves “target enrichment,” where specialized probes are used to capture only the exonic regions of the fragmented DNA. The enriched exonic DNA fragments are then sequenced using high-throughput, massively parallel sequencing technologies. This technology allows millions of DNA sequences to be read simultaneously.
The raw sequencing data generated from this process is extensive and requires sophisticated bioinformatics analysis. This analysis involves aligning the sequenced reads to a human reference genome, identifying differences (variants) between the patient’s DNA and the reference, and then filtering these variants to pinpoint those that might be disease-causing. This computational filtering process helps narrow down the approximately 20,000 variants typically found per patient to a manageable number for clinical interpretation.
Interpreting Clinical Exome Sequencing Results
A clinical exome sequencing report provides detailed information about identified genetic variations, categorized by their significance. Pathogenic or likely pathogenic variants are those that are strongly believed to cause or contribute to the patient’s condition.
Variants of uncertain significance (VUS) represent genetic changes whose impact on gene function and disease risk is not yet clearly understood. These variants require further investigation and may be reclassified over time as more scientific evidence becomes available. Incidental or secondary findings are another category, representing genetic variations that are unrelated to the initial reason for testing but may have medical implications for the patient’s current or future health. Patients can choose whether to receive information about these secondary findings.
Interpreting these complex results requires specialized expertise, and genetic counseling is an important part of the process. Genetic counselors help patients understand the implications of their results, including the probability of a diagnosis, the nature of any identified variants, and potential future health risks. They also discuss the possibility of non-diagnostic results, where no clear genetic cause is found, and the ongoing nature of genetic interpretation as scientific knowledge evolves.
Practical Considerations and Limitations
The turnaround time for clinical exome sequencing results can vary, typically ranging from a few weeks to several months, with some expedited options providing results within about two weeks. This timeframe depends on the laboratory’s workflow and the complexity of the analysis.
Clinical exome sequencing may not always yield a definitive diagnosis; approximately 44% to 70% of patients may not receive a specific genetic diagnosis after initial testing. This can be due to the limitations of current sequencing technology, the location of disease-causing variants in non-coding regions not fully covered by exome sequencing, or the fact that some identified variants are in genes not yet associated with known diseases. The financial cost associated with clinical exome sequencing can be a consideration, though it can be a cost-effective approach compared to a series of individual targeted tests. Expert interpretation, including by genetic counselors, is recommended for understanding these results and their implications.