Table 2.

Genetic testing approaches

Type of genetic testingLevel of analysisWhen usedAdvantagesLimitations/disadvantages
Familial variant testing of a single geneAnalysis of a single variantKnown familial variantLeast expensiveMay miss a cancer-predisposing mutation in a different gene not previously identified in the individual or family (a rare circumstance)
Very accurateTesting should be performed in the same lab that identified the mutation in a family member, or a positive control sample should be sent
Results are definitive
Single geneaSanger sequencing or NGS coding sequence and intron/exon borders of the selected genePhenotype fits a known cancer syndrome caused by one or a few genesHighly specificMay not identify certain types of variants (i.e., deep intronic variants)
+/− copy number analysis for intragenic deletions/duplicationsLower risk for VUSMay miss variants in more rarely associated genes not tested with this approach
Additional testing may be required if initial testing is negative or inconclusive
Multigene panelaNGS of coding sequence and intron/exon borders of the selected genesPhenotype that does not clearly fit with a specific syndromeIncreases the chance of identifying a causative variantMay identify incidental findings/VUS
May include targeted panel of genes associated with specific cancer type or broad panel of genes associated with cancer predispositionPatients suspected to have a condition that can be associated with variants in multiple genes (e.g., pheochromocytoma/paraganglioma)Cost-effectiveDepending on nature of the panel, may identify moderate-risk genes for which limited surveillance recommendations may be available
+/− copy number analysis for intragenic deletions/duplications
WES/WGSaNGS technology to evaluate coding areas (exons and intron/exon borders only) or entire genome (exons and introns)Patients with unclear cancer phenotypes or multisystem phenotypesCost of WES/WGS is approaching the cost of multigene panels and may be the most cost-effective approach in the futureNot all platforms will have adequate coverage of the genes of greatest interest for a patient
Patients with negative/uninformative results on prior single-gene or multigene testingData can be reanalyzed as new genetic associations are madeSequencing technology may miss intragenic copy number variants
Research settings identify novel genetic associationsGreatest chance for incidental findings/VUS
Ethical considerations regarding possible identification of variants associated with adulthood disease risk
Challenges in storing and reinterpreting data and communicating implications over time
Increased time to obtain informed consent and determine preference for possible result types
NGS technologies not consistently available as a clinically certified test
SNP MicroarrayGenome-wide microarray to detect large chromosomal deletions/duplicationsPatients with developmental delays/intellectual disability/autism spectrum disorder and/or congenital abnormalities that may be indicative of a chromosomal deletion/duplicationIdentifies large deletions or duplications that may be missed by single-gene, multigene, or WES/WGS testingChance of incidental findings (including consanguinity)/VUS
Patients identified by single-gene or multigene testing to have a whole gene deletionDefines size of deletion or duplication and genes includedWill not identify balanced chromosomal rearrangements
Will not identify sequence alterations or deletions/duplications below a certain size
  • Abbreviation: WES/WGS, whole exome sequencing/whole genome sequencing.

  • aNGS-based testing has the ability to detect mosaicism due to a de novo mutation.