Genetic testing is not a single technology. Different tests examine different portions of the genome, at different levels of detail, for different purposes. Understanding how whole genome sequencing (WGS) fits into this landscape helps patients and clinicians make better decisions about which test is most appropriate.

The Spectrum of Genetic Tests

Single-Gene Tests

The simplest genetic tests examine one specific gene for variants associated with a particular condition. A single-gene test for BRCA1 would look only at that gene. Single-gene tests are appropriate when there is a strong clinical reason to focus on one specific gene — for example, when a specific pathogenic variant has already been identified in a family member.

Multi-Gene Panels

Multi-gene panels test a defined set of genes simultaneously. A hereditary breast and ovarian cancer panel might include BRCA1, BRCA2, PALB2, ATM, CHEK2, and other relevant genes. A Lynch syndrome panel would include the mismatch repair genes.

Panels are efficient when the clinical question is well-defined. Their limitation is that they only examine the genes included in the panel — anything outside the panel is not tested.

Chromosomal Microarray

Chromosomal microarray (CMA) detects large deletions and duplications across the genome — changes involving thousands to millions of base pairs. It does not read the DNA sequence letter by letter. CMA is commonly used in the evaluation of developmental delay, intellectual disability, and congenital anomalies.

Exome Sequencing

Exome sequencing reads the protein-coding portions of the genome — the exons — which represent approximately 1–2% of the total genome but contain the majority of currently known disease-causing variants. Exome sequencing is more comprehensive than a panel but does not capture non-coding regions.

Whole Genome Sequencing

Whole genome sequencing reads all approximately 6 billion base pairs of DNA — both the protein-coding exons and the non-coding regions between and around genes.

WGS can detect:

• Single nucleotide variants (SNVs) — single-letter changes
• Small insertions and deletions (indels)
• Copy number variants (CNVs) — large deletions and duplications
• Structural variants — larger rearrangements
• Variants in non-coding regulatory regions

The non-coding genome is not simply "junk DNA." It contains regulatory sequences that control when and how much of a gene is expressed. Variants in these regions can cause disease, and only WGS can reliably detect them.

How WGS Differs From Exome Sequencing

The key difference is coverage. Exome sequencing covers approximately 1–2% of the genome. WGS covers essentially all of it.

In practice, this means WGS can detect variants that exome sequencing misses — particularly in regulatory regions, deep intronic sequences, and areas of the genome that are technically difficult to capture with exome enrichment methods.

WGS also provides more uniform coverage across the genome, reducing the chance of missing variants in regions that are poorly captured by exome enrichment.

When Does WGS Add the Most Value?

WGS is particularly valuable when:

• A patient has a condition that has not been explained by previous targeted testing
• There is reason to suspect a variant in a non-coding region
• Comprehensive baseline genomic information is desired for future reference
• The clinical question is broad rather than focused on a specific gene or condition

For focused clinical questions — such as "does this patient have a BRCA variant?" — a targeted panel may be more efficient and cost-effective.

Interpretation Remains the Critical Step

Generating a whole genome sequence is now technically feasible and increasingly affordable. The harder challenge is interpretation.

A whole genome sequence contains millions of variants. The vast majority are benign. Identifying which variants are clinically significant — and explaining what they mean for a specific patient — requires expertise in medical genetics, familiarity with current evidence, and careful integration with the patient's personal and family history.

At Genetic Insights, we offer whole genome sequencing with expert interpretation by Dr. Michael P. Vaughn, a physician with a PhD in biochemistry and decades of experience in medical genetics.

Key Takeaway: Whole genome sequencing reads all 6 billion base pairs of DNA, including non-coding regions that other tests miss. Its value lies not just in the data it generates but in expert interpretation of what that data means for a specific patient.

Sources: NHGRI Whole Genome Sequencing Fact Sheet; GeneReviews — Approach to Genomic Diagnosis