Exome sequencing is most useful when the phenotype guides interpretation
Whole-exome sequencing examines much of the protein-coding portion of the genome. It can test many genes at once when symptoms overlap several disorders or previous targeted tests were unrevealing.
A negative result does not exclude a genetic disorder. Some variants, repeat expansions, structural changes, mitochondrial findings or non-coding causes may not be detected reliably, and interpretation depends on current knowledge.
Testing an affected person with biological parents can help classify new, recessive and inherited variants, but it may also reveal unexpected family relationships.
Who may be considered?
This review may help when the phenotype and existing evidence create a focused question about clinical exome sequencing or reanalysis.
- A multisystem or developmental condition without a diagnosis.
- A suspected genetic disorder with many possible genes.
- A prior negative panel where broader coding analysis is justified.
- A previously negative exome suitable for reanalysis.
- A family seeking segregation testing for a candidate variant.
What the specialist team must confirm
Clinical geneticists review detailed features using standardized terms, onset and progression, pedigree, prior tests, sample availability, consent preferences and whether exome limitations fit the diagnostic question.
Key points for this treatment
From phenotype to a defensible molecular conclusion
Laboratory analysis and clinical interpretation are linked, with confirmatory testing and family studies used when they can resolve uncertainty.
Results, family implications and reanalysis
A pathogenic or likely pathogenic finding is checked against the phenotype and may guide care, surveillance or family testing. A variant of uncertain significance should not be treated as a confirmed diagnosis.
Negative and uncertain exomes can be reconsidered when features evolve or gene-disease knowledge changes. The laboratory should explain whether raw data are retained and how reanalysis is requested.
Limits, burdens and realistic expectations
Exome coverage is uneven and many variant types may be missed. Interpretation can change, incidental findings may arise, and a molecular diagnosis does not guarantee treatment. Privacy and family implications require informed consent.
Do not delay treatment of seizures, metabolic decompensation, breathing problems or other acute complications while waiting for sequencing.