Patient and family counselling regarding findings of variants of uncertain significance (VOUS) and incidental findings in genetic testing - need for family studies

Why family studies help

When a VOUS is identified, testing additional family members (segregation studies) can help resolve its classification - if the variant is found to track consistently with the disease phenotype across multiple affected and unaffected relatives, this strengthens the case for pathogenicity (or, if it does not segregate, for benignity)
Family segregation studies are one of the more powerful tools available to reclassify a VOUS, particularly in families with several living affected and unaffected relatives willing to be tested

If a variant is present in multiple affected relatives but absent in unaffected relatives across a large enough family, this statistically supports pathogenicity; conversely, if the variant is found in unaffected, unrelated, or non-segregating family members, this supports reclassification toward benign

Requires identifying and approaching relevant relatives (both affected and, importantly, unaffected) for testing, with appropriate informed consent for each - a process that takes time, family engagement, and often coordination across a geographically dispersed family
Segregation evidence is only useful with an accurately constructed pedigree/genogram and correctly documented clinical status (affected/unaffected) for each relative tested

Genetics services typically coordinate this process systematically, since it usually requires sequential/parallel testing of several relatives rather than a single additional test - and requires clear counselling with each relative about why they are being asked to test and what the result will (and will not) mean for them personally

Cascade testing, pedigree/genogram construction, VOUS reclassification over time

Family segregation studies are most powerful in large families with multiple affected individuals - in a small family or with a de novo (sporadic) presentation, segregation testing has limited power to help resolve the classification, and other evidence types become relatively more important

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