Microarray vs Whole-Exome Sequencing (WES): Which Genetic Test is Right for Rare Disease Diagnosis?

In this article, we explore the key differences between Microarray and WES, highlighting their respective roles in diagnosing rare diseases and how they can complement each other for more comprehensive evaluations.

Chromosomal Microarray Test

Chromosomal Microarray Analysis (CMA) is a high-resolution genetic test used to detect copy number variations (CNVs), such as deletions or duplications, across the entire genome.

CMA is widely used in clinical diagnostics for genetic disorders, particularly for conditions involving developmental delays, intellectual disabilities, congenital anomalies, and other genetic syndromes.

Limitations of Microarrays for Rare Disease Diagnosis

1. Limited Resolution

Microarrays are adept at identifying large copy number variations (CNVs), but they are less effective in detecting small insertions or deletions (indels) and finer structural changes. Some rare diseases are caused by these subtle genetic alterations, which microarrays may overlook. As a result, patients might require further testing if microarray results do not provide a diagnosis.

2. Missed Variants

Microarrays rely on pre-designed probes that target known genetic regions, which means that novel or rare genetic variants not included in the probe design may be missed. This targeted approach can result in false negatives, especially when the rare disease is caused by less understood genetic mutations.

3. Limited Coverage of Non-Coding Regions

While microarrays are excellent for analyzing coding regions (where most genes are located), they offer limited coverage of non-coding regions, which make up a significant portion of the genome. Variants in these non-coding regions, such as regulatory elements, can impact gene expression and contribute to rare diseases, but they are often missed by microarrays.

4. Lack of Flexibility

The predefined genetic panels used in microarrays cannot be easily updated as new disease-causing variants are discovered. This lack of adaptability limits microarrays in keeping pace with the latest genetic research, requiring supplemental testing through more advanced methods.

Whole-Exome Sequencing (WES): A Comprehensive Alternative

Whole-Exome Sequencing (WES) is a more comprehensive approach, analyzing all the coding regions (exons) of the genome. This method covers approximately 1-2% of the genome, but these regions contain about 85% of disease-causing variants. WES has become a popular diagnostic tool for rare diseases due to its ability to identify not only known genetic mutations but also novel or rare variants, small indels, and even structural rearrangements that microarrays might miss.

Key Advantages of WES Over Microarray

1. Detection of Rare and Novel Variants

Unlike microarrays, which are limited to detecting known variants, WES analyzes the entire coding region, enabling it to uncover rare, novel, or previously unidentified genetic mutations. This makes WES a highly valuable tool for diagnosing rare diseases that may be caused by variants not covered in microarray panels.

2. Increased Sensitivity for Small Variants

WES is more sensitive than microarrays for detecting small insertions, deletions, and point mutations. It provides a more detailed analysis of the genome, identifying smaller-scale alterations that might be responsible for a patient’s condition.

3. Coverage of Coding Regions

While WES focuses only on exons, where most disease-causing mutations occur, its coverage is more comprehensive than microarrays. This broader scope allows for a deeper investigation into the genetic basis of rare diseases.

4. Adaptability and Customization

WES technology is adaptable and can be updated as new genetic variants are discovered. This flexibility allows for ongoing improvements in diagnostic accuracy, ensuring that patients receive the most up-to-date genetic insights.

When to Consider Microarray vs WES

• Microarray is particularly useful for diagnosing conditions related to large chromosomal abnormalities, such as deletions, duplications, and unbalanced rearrangements. It remains a cost-effective and fast option for identifying known CNVs and SNPs in the genome.

• WES, on the other hand, should be considered when a rare disease is suspected, but a previous microarray analysis yielded inconclusive results. WES is ideal for detecting point mutations, small indels, and novel genetic variants that are not captured by microarrays. It is especially valuable for cases where the clinical picture points to a genetic cause that is hard to identify through other methods.

What Makes 3B-EXOME Stand Out?

Our tailored and advanced exome sequencing is designed to enhance diagnostic precision.

• Improved Detection of Critical Pathogenic Variants: Captures essential pathogenic variants that are often overlooked within exon regions, such as the ORF15 exon of the RPGR gene.
• Inclusion of Intron Regions: Recognizing that significant disease-causing mutations can occur in non-coding regions, 3B-EXOME incorporates these areas, offering a more comprehensive genetic analysis.
• Extensive Gene Coverage for Therapeutic Targets: Provides full sequencing coverage of genes targeted by treatments, including those for Fabry disease (GLA gene) and Leber congenital amaurosis (RPE65 gene).
• Mitochondrial DNA (mtDNA) Analysis: Unlike other tests that require a separate analysis for mtDNA, 3B-EXOME includes mtDNA regions, delivering a complete solution for genetic diagnostics.
• Ongoing Reanalysis: Offers continuous reanalysis for cases that remain undiagnosed, ensuring up-to-date insights as new data emerge.