When next-generation sequencing finds a change in a gene that is already well understood and clearly linked to a person’s symptoms, it is highly accurate and reliable. However, families should understand from the outset that a genetic diagnosis is not guaranteed even with the broadest form of this testing. Across large clinical studies, whole exome sequencing identifies a clear genetic cause in roughly 3-in-10 to 4-in-10 children tested for unexplained developmental or congenital conditions; testing both parents alongside the child, known as trio sequencing, raises this further, since it is much easier to tell whether a variant is new, inherited, or simply a harmless family variation when both parents’ sequences are available for comparison. Whole genome sequencing adds a further increase in yield, on the order of 1-in-20 to 1-in-10 additional cases identified beyond exome sequencing alone, largely by catching changes in the non-coding regions between genes and structural changes that whole exome sequencing is not designed to see. Even so, more than half of children tested will not receive a clear genetic answer on a first round of testing, which is one of the most important points to discuss beforehand.

A second important limitation is the variant of uncertain significance: a genetic change that is real and confirmed, but for which there is not yet enough scientific evidence to say whether it is harmless or disease-causing. Because next-generation sequencing reads so much of the genetic code at once, this kind of ambiguous finding is considerably more common than with older, narrower tests, and a geneticist will explain clearly when a reported finding falls into this uncertain category rather than being a confirmed cause.

Third, broader forms of this testing, particularly whole exome and whole genome sequencing, can uncover what are called secondary findings: genuine, medically significant findings unrelated to the original reason for testing, such as a gene associated with a treatable heart condition or a hereditary cancer risk. The American College of Medical Genetics and Genomics maintains a specific list, currently covering eighty-four genes linked to conditions where early knowledge changes management, and families are always offered the choice, discussed during pre-test genetic counseling, of whether they wish to receive this kind of unrelated information at all.

Finally, results and their interpretation are not always permanent. As scientific understanding grows, a variant once labelled uncertain is often later reclassified, in either direction, which is why families are encouraged to stay in contact with their genetics team over time.