If a genetic test is negative but clinical suspicion is strong, which statement is true?

• A. The patient definitely does not have a genetic condition
• B. The negative result excludes variants in all genes
• C. A negative result does not exclude a genetic cause; consider other genes, noncoding variants, polygenic risk, or testing limitations
• D. The test must be repeated with the same panel

Answer: (C)

When clinical suspicion remains high despite a negative test, it’s important to recognize that the result does not rule out a genetic cause. Genetic testing has limitations in what it can detect and how broad its reach is. A negative result can occur because the test didn’t include the responsible gene, the variant lies outside the captured regions (for example, in noncoding or regulatory areas), or it’s a type not easily detected by standard methods (such as deep intronic variants, structural changes, or mosaicism). Additionally, knowledge about genes and variants evolves, so reanalysis or broader testing (like exome or genome sequencing with CNV and noncoding-region analysis) may uncover a cause later. In some scenarios, multiple common variants with small effects contribute to a phenotype, so a single-gene test won’t capture the full genetic contribution. Overall, a negative result does not exclude a genetic cause; consider expanding testing, exploring noncoding regions, evaluating polygenic risk where appropriate, and allowing for reanalysis as new information becomes available.