Next-generation sequencing is used across a wide range of clinical situations, unified by the fact that many different genes could plausibly explain what is being seen:

• Children with unexplained developmental delay, intellectual disability, or autism. Because well over one thousand different genes have been linked to these presentations, testing one gene at a time is rarely practical, and whole exome or whole genome sequencing is now recommended as an early, and often first-tier, test in this group by the American College of Medical Genetics and Genomics.
• Children or adults with multiple, unexplained physical or birth differences affecting more than one body system, where a single unifying genetic cause is being sought and no one condition is obviously suspected on clinical grounds alone.
• Families with a condition that is genetically varied, such as certain inherited forms of epilepsy, hearing loss, kidney disease, cardiomyopathy, or vision loss, where dozens or hundreds of different genes can each cause a similar-looking condition, making a targeted gene panel or broader sequencing far more efficient than testing genes individually.
• Individuals or families with a personal or family history suggesting hereditary cancer risk, where a gene panel covering the genes most strongly linked to that cancer type is commonly used to guide screening and, for relatives, decisions about future testing.
• Pregnancies with a structural finding on ultrasound that other tests have not explained. When chromosomal microarray has already been performed and has not clarified the finding, whole exome sequencing focused on the pregnancy is sometimes offered, most often through specialist fetal medicine and genetics teams.
• Cancer tissue itself, in oncology care. Sequencing a tumor sample, as distinct from testing a person’s inherited DNA, can identify the specific genetic changes driving that particular cancer, which increasingly guides the choice of targeted medication.

Across all of these situations, next-generation sequencing is chosen because the list of genes that could be responsible is long enough, or specific enough, that reading many genes together, rather than guessing at one, gives families the best realistic chance at an answer, and a geneticist or genetic counselor helps decide which form of the test, a gene panel, whole exome sequencing, or whole genome sequencing, best fits the situation.