How Accurate Is FISH Testing?

[Anonymous]

How accurate is FISH testing, and could it come back with a result that does not fully answer my question?

[Genetic Counselor]

When FISH is used for the exact purpose, it is designed for, checking one known, well-characterized region, it is highly accurate. Laboratory standards set by the ACMG require that each probe be validated for at least 95% sensitivity before it is used clinically, and testing of relatives for an already-confirmed familial change typically approaches 100% reliability, since the laboratory knows exactly what pattern it is looking for and has a known comparison available.

The accuracy of this test is tightly bound to its focus, however, and this is the single most important limitation for families to understand. A normal result only rules out the one specific change the probe was designed to detect; it says nothing about the rest of that person’s genetic material. As an example, in 22q11.2 deletion syndrome, the standard fluorescence in situ hybridization probes target a defined stretch of the chromosome, and they can miss an estimated 5-15% of cases where the deletion is unusually positioned outside that exact stretch, even though the person has genuinely inherited a clinically significant version of the same condition. For this reason, when a family’s situation is not already narrowed down to one clear possibility, chromosomal microarray or sequencing-based testing, which survey much more of the genome at once, are generally recommended as the more complete first test, with fluorescence in situ hybridization reserved for situations where speed or an already-known target makes it the better tool.

This test also has a resolution limit; it cannot detect a change within a single gene, such as one altered letter of the genetic code, and it can miss a genetic change that is present in only a small proportion of a person’s cells, a situation called low-level mosaicism, if too few cells are examined. Because interphase testing on non-dividing cells is what makes rapid results possible, results from this approach are also generally treated as preliminary in pregnancy, with a complete chromosome analysis performed afterward to confirm the finding and check for anything the targeted test could not see. As with any genetic test, a geneticist or genetic counsellor reviewing the specific probes used and what they can and cannot rule out is an essential part of understanding what a result truly means.

[Author]

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