What can whole genome sequencing check that is not detected by whole exome seq

[Anonymous]

What can whole genome sequencing check that can’t be detected by whole exome sequencing?

[Genetic Counselor]

Because whole genome sequencing reads virtually the entire genetic code rather than only the coding exome, it can pick up several categories of genetic change that whole exome sequencing is not designed to see well:

• Structural rearrangements, such as inversions, where a segment of a chromosome is flipped or repositioned without any genetic material actually being gained or lost. Whole exome sequencing reads short, disconnected stretches of coding DNA, which makes it poorly suited to recognizing this kind of large-scale rearrangement. Whole genome sequencing reads DNA in a far more continuous way, which makes it considerably better at catching changes like this.
• Disease-causing changes in the regulatory and splicing-relevant regions that surround genes. Not every disease-causing change lies within the stretch of DNA that is directly translated into protein; some sit in nearby regions that act as switches, controlling when and how strongly a gene is used, or that control how a gene’s instructions are correctly edited together. Because whole exome sequencing does not read these surrounding regions at all, a change located there is simply invisible to it.
• Certain repeat expansion disorders. A number of genetic conditions are caused not by a single altered letter but by a short sequence of letters that repeats far more times than it normally should, a pattern that whole exome sequencing’s capture-based approach is not well suited to detecting reliably.
• At least some information from the mitochondrial genome, the small, separate set of genetic instructions carried inside mitochondria, the structures that produce energy for the cell. Because whole exome sequencing’s capture step targets only coding DNA within the cell’s main genetic material, it generally does not capture mitochondrial sequence at all, while whole genome sequencing, reading DNA more broadly, can pick up at least some of this information as a byproduct.

These advantages come with practical trade-offs. Detecting a mitochondrial change present in only a small fraction of a person’s cells, a situation called heteroplasmy, at very low levels can still require dedicated mitochondrial-specific testing performed at much greater depth than a standard whole genome sequencing run provides, and a larger volume of data overall means more findings of every kind, including ones that take longer to classify. A geneticist weighs whether these specific categories of genetic change are plausible enough in a given family’s situation to justify choosing whole genome sequencing over the narrower, generally faster and less expensive whole exome sequencing.

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