Match the suspected disease mechanism to what the assay can evaluate. The broadest-sounding test is not automatically the most informative choice, and a negative result does not exclude mechanisms the assay did not assess.
Compare the question each method can answer
| Method | Core question | Important limit |
|---|---|---|
| Karyotype | Is there a visible chromosome number or structural change? | Resolution is limited for small changes |
| Chromosomal microarray | Is there a detectable dosage change across the genome? | Balanced rearrangements generally are not detected |
| Targeted or panel sequencing | Is there a relevant sequence variant in the assessed genes? | Coverage and included variant classes vary |
| Exome sequencing | Is there a relevant sequence variant in the protein-coding regions assessed? | Assessed regions and variant classes vary; noncoding and some structural variants may be missed |
| Genome sequencing | Is there an explanation within a broader analysis, including selected noncoding regions? | Broader coverage does not guarantee detection of every mechanism or interpretable variant |
| Methylation analysis | Is there an abnormal methylation pattern at the assessed locus? | It does not necessarily identify the underlying cause by itself |
Confirm the laboratory's actual methods. Some sequencing assays also evaluate copy-number or other variant classes; others do not. SNP-based arrays can provide information beyond dosage, but that does not make them a universal test for imprinting disorders.
Practice case: an unresolved imprinting question
A sequencing report is negative, but a child's findings continue to suggest an imprinting disorder. The laboratory confirms that methylation was not assessed. The reasoning task is to identify the mechanism still unevaluated, rather than assuming the negative result settles the diagnosis.
For suspected Prader-Willi syndrome, the current GeneReviews chapter describes first-tier evaluation with DNA methylation analysis and an oligo-SNP array. This condition-specific approach illustrates why test selection should follow the suspected mechanism and current reference.
Practice case: broad developmental findings
A child has developmental delay and congenital anomalies without a clear single-gene diagnosis. The ACMG guideline supports considering exome or genome sequencing as a first- or second-tier test in its defined pediatric CA/DD/ID population. This does not mean every developmental presentation needs an identical testing sequence; phenotype, prior studies, and assay capabilities still matter.
Use EveryGene Academy for application, 101 Must-Know Genetic Conditions flashcards for condition context, and the free pedigree workbook for family-risk reasoning.
Sources: NHGRI genetics glossary; MedlinePlus on genetic testing; ACMG 2021 chromosomal microarray technical standard; ACMG pediatric exome/genome sequencing guideline; Prader-Willi syndrome GeneReviews. Confirm the laboratory's actual methods for any real case.
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