In cascade testing, which relative is typically tested first?

• A. First-degree relatives.
• B. Second-degree relatives.
• C. Third-degree relatives.
• D. Unrelated individuals with similar presentation.

Answer: (A)

Cascade testing starts with the closest relatives because they offer the most informative and efficient step in mapping a familial variant. First-degree relatives share about 50% of their genetic material with the affected individual, so they have the highest prior probability of carrying a pathogenic variant identified in the family. Testing them first confirms whether the variant is present in the immediate lineage and establishes whether the family’s variant is segregating with disease. Once the variant is confirmed in a first-degree relative, testing can be directed at more distant relatives using a targeted test for that known variant, which is faster, cheaper, and more informative than broad, non-targeted testing. This approach also helps with risk assessment and management decisions for relatives who are most closely connected to the proband.