Question

Whole Exome Sequencing (WES) is becoming a procedure to help physicians identify the cause of a genetic condition that has defied diagnosis by traditional means. The implication here is that exons in the nuclear genome are sequenced in the hopes that, by comparison with the genomes of nonaffected individuals, a diagnosis might be revealed. (a) What are the strengths and weaknesses of this approach? (b) If you were ordering WES for a patient, would you also include an analysis of the patient's mitochondrial genome?

Short answer

Answer: The strengths of WES include cost-effectiveness, functional relevance, and reduced data complexity. Weaknesses of WES involve not capturing non-coding regions, technical limitations, and difficulty in interpreting results. It is essential to include the analysis of a patient's mitochondrial genome when ordering WES because it can reveal information about mitochondrial disorders, heteroplasmy, and inheritance patterns.

Step-by-step solution

(a) Strengths of WES

Whole Exome Sequencing provides several benefits in the field of genetics, which include: 1. Cost-Effectiveness: WES is less expensive than Whole Genome Sequencing, as it only targets the protein-coding regions. 2. Functional relevance: Since exons code for proteins, WES mainly targets the functionally relevant parts of the genome, improving the chances of identifying the cause of a genetic condition. 3. Reducing data complexity: WES produces a smaller dataset compared to Whole Genome Sequencing, making data storage, processing, and analysis more efficient.

(a) Weaknesses of WES

Despite the advantages, there are also several limitations of WES: 1. Non-coding regions not captured: WES only focuses on coding regions, so it might miss gene regulatory elements located in non-coding regions, which can also play a crucial role in genetic conditions. 2. Technical limitations: There may be errors during sequencing due to low coverage, making it potentially difficult to find the actual cause of genetic conditions. 3. Difficulty in interpreting results: Rare variants or novel mutations may not have clear functional implications, making interpretation of WES results challenging for healthcare providers.

(b) Analysis of the patient's mitochondrial genome

Yes, it's essential to include the analysis of the patient's mitochondrial genome when ordering WES for the following reasons: 1. Mitochondrial disorders: Mitochondrial DNA mutations can cause a variety of genetic conditions, and excluding the mitochondrial genome would leave out an important source of genetic information. 2. Heteroplasmy: Unlike nuclear DNA, mitochondrial DNA can exhibit heteroplasmy, which means that an individual can have more than one type of mitochondrial DNA. Including the mitochondrial genome analysis helps to identify potential heteroplasmic mutations contributing to the disease. 3. Inheritance patterns: Mitochondrial disorders are maternally inherited, so analyzing the mitochondrial genome can provide essential information about the inheritance patterns and recurrence risks of the genetic condition within a family.