Who actually needs whole exome sequencing, when is it done as a “trio” ?

[Anonymous]

Who actually needs whole exome sequencing, and when is it done as a “trio” with both parents?

[Genetic Counselor]

Whole exome sequencing is used across several distinct clinical situations, unified by the fact that a broad, unbiased search across the coding genome offers a realistic chance of an answer where testing genes one at a time does not:

• Children with unexplained developmental delay, intellectual disability, or multiple congenital anomalies. Because well over a thousand different genes have been linked to these presentations, the American College of Medical Genetics and Genomics recommends whole exome sequencing, or whole genome sequencing, as an appropriate first-tier or early test in this group, rather than working through smaller panels first.
• Families with a suspected single-gene condition where the list of candidate genes is too broad for a panel. This includes many inherited forms of epilepsy, kidney disease, hearing loss, and neuromuscular conditions, where dozens or hundreds of genes can each produce a similar clinical picture.
• Pregnancies with a structural finding on ultrasound that remains unexplained after other testing. Professional guidance is clear that fetal whole exome sequencing is not a first-line prenatal test; it is considered only after karyotyping and chromosomal microarray have already been performed and have not clarified the finding, and is generally offered through specialist fetal medicine and genetics teams.
• Adults with an undiagnosed condition that has resisted years of individual gene testing, particularly when the presentation crosses body systems in a way that does not fit a single well-recognized syndrome.

Whenever possible, whole exome sequencing is performed as a “trio,” meaning the affected person and both biological parents are sequenced together, rather than the affected person alone. This matters because most disease-causing changes found through this test are compared against a person’s genetic background to determine whether a variant is newly arisen, called de novo, inherited from an unaffected parent and therefore less likely to be significant on its own, or shared with a parent who has related symptoms. Having both parents’ sequences available makes this comparison far faster and more reliable, and trio testing consistently identifies a genetic cause more often than testing the affected person alone. When both biological parents are not available, for reasons including donor conception, adoption, or a parent’s own preference, proband-only, or “solo,” exome sequencing is still a valid and commonly used option, sometimes followed later by targeted testing of relatives once a candidate variant has been identified.

[Author]

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