Opening situation
There is a particular kind of silence in medical genetics.
The silence that follows a “negative” exome in a child whose phenotype is unmistakable.
The clinical signs are there.
The neurological trajectory is recognizable.
The phenotype feels coherent.
Yet the report says: negative.
For clinicians and families, this moment can be deeply disorienting.
Expectations had been building. And still, the answer does not arrive.
The biology seems consistent.
But the analysis appears to disagree.
Or perhaps the analysis has simply reached the limits of what it was designed to see
Why this happens
Whole Exome Sequencing focuses on the protein-coding regions of the genome.
These regions contain the majority of disease-causing variants, which is why exome sequencing is one of the most powerful tools in rare disease diagnostics.
However, not all pathogenic variants lie within the exome.
Some relevant alterations can remain invisible to the exome: deep intronic variants, complex rearrangements, regulatory alterations outside the coding regions.
When the phenotype strongly suggests a genetic cause, a negative exome does not necessarily close the investigation.
Sometimes it simply indicates that the relevant information lies elsewhere in the genome.
The genomic turning point
In some cases, the next step is Whole Genome Sequencing (WGS).
Unlike exome sequencing, WGS analyzes the entire genomic sequence, including regions that standard exome approaches do not capture.
This broader perspective can reveal alterations that remain invisible in exome data.
In one such case, the genome revealed what the exome could not detect:
• a structural deletion on one allele
• a deep intronic variant on the other
Together, these alterations disrupted the same gene.
The exome had not been wrong.
It had simply been incomplete.
THE CLINICAL DECISION
Sometimes the key decision is knowing when to change scale.
Moving from exome to genome is a decision about how far the investigation
must go.
THE CLINICAL DECISION
Sometimes the key decision is knowing when to change scale.
Moving from exome to genome is a decision about how far the investigation
must go.
THE CLINICAL DECISION
Sometimes the key decision is knowing when to change scale.
Moving from exome to genome is a decision about how far the investigation must go.
The clinical takeaway
Genomic analysis should never be treated as a purely technical procedure.
When the phenotype strongly suggests a genetic origin,
the diagnostic trajectory ca be adjusted and eventually expanded:
• re-evaluation of the exome
• expansion to genome sequencing
• integration of newly acquired clinical information