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Choosing the right genetic test matters because each method detects a different scale of genetic abnormality, from whole extra chromosomes down to a single altered gene. Karyotyping, FISH (fluorescence in situ hybridisation), and PCR (polymerase chain reaction) are three genetic tests that work at progressively finer levels of detail. For example, imagine a child with distinctive facial features and a heart defect, suspected to have a small missing piece of chromosome 22: a standard karyotype is too coarse to see it, so a more targeted test is needed. In practice, matching the suspected condition's scale to the right test avoids a false-negative result from testing too coarsely.

Karyotyping images and counts whole chromosomes under a microscope, and detects aneuploidy (an abnormal chromosome number), such as trisomy 21 in Down syndrome, or large structural rearrangements. FISH (fluorescence in situ hybridisation) uses a fluorescent probe that binds to a specific small region of a chromosome, detecting microdeletions too small for a standard karyotype to see. An example is the 22q11 deletion, a missing piece of chromosome 22 linked to a syndrome with heart defects, immune problems, and raised psychosis risk. PCR (polymerase chain reaction) amplifies a specific short stretch of DNA, making it useful for detecting single-gene changes and trinucleotide repeat expansions (an abnormally long repeated three-letter DNA sequence), such as in Fragile X syndrome. Picture a young man with intellectual disability, a long face, and large ears: PCR testing for a repeat expansion in the FMR1 gene confirms Fragile X syndrome, a diagnosis a karyotype alone would miss. In practice, ordering the wrong test, such as a karyotype for a condition that actually needs PCR, produces a falsely reassuring normal result.

• Which test is now first-line for a child with unexplained developmental delay and dysmorphic features?
• What kind of abnormality will a standard karyotype fail to detect?
• Which test examines the protein-coding regions across all genes at once?

• Karyotype, detects whole-chromosome abnormalities such as trisomy 21, unlike FISH which detects much smaller deletions.
• FISH, detects microdeletions such as 22q11, whereas PCR detects single-gene changes and repeat expansions rather than chromosome-level changes.
• PCR, identifies trinucleotide repeat expansions such as Fragile X syndrome, rather than the whole-chromosome or deletion-level abnormalities karyotype and FISH detect.
• 22q11 deletion syndrome, requires FISH or a similar targeted test to detect, unlike Down syndrome which a standard karyotype reliably identifies.

• Imaging identifies structural brain change rather than a genetic cause.
• Karyotyping views whole chromosomes rather than sequence.
• A karyotype resolves only changes of roughly five million bases or larger.
• Single gene testing requires a specific clinical hypothesis.
• A blood count gives no genetic information.

• Localise the clue to the relevant anatomical level, cell type, pathway or molecular process.
• Map that structure or process to its normal function.
• Predict the deficit or clinical sign produced when it is disrupted.
• Reject options that belong to a neighbouring structure, pathway or level of explanation.