Article|Articles in Press, 100818

Cascade testing following exome sequencing: Retrospective analysis of linked family data at two US laboratories

Published:February 24, 2023DOI:
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      Cascade testing, the process of testing a proband’s at-risk relatives, is integral to realizing the full value of genomic sequencing. However, there is little empirical evidence on the uptake of cascade testing after positive exome sequencing (ES) in a population of probands with diverse clinical indications.


      We retrospectively reviewed administrative data from two US clinical laboratories that perform ES. For each proband with a positive ES result, we used linked family data to describe the frequency of relatives’ cascade testing performed at the same laboratory, variant detection yield of cascade tests, and characteristics of probands and relatives categorized based on cascade testing completion.


      Among 3,723 positive ES across both laboratories, 426 relatives of 282 probands completed cascade testing (uptake: 7.6%). An average of 1.5 relatives (SD 0.9) were tested per proband. Among the 426 relatives tested, 200 had a variant of interest detected (variant detection yield: 47.0%).


      In our real-world data analysis, a small proportion of probands with a positive ES subsequently had relatives complete cascade testing at the same laboratory. However, approximately half of the relatives tested received a clinically significant result that could have implications for clinical management or reproductive planning. Additional research on ways to increase uptake is warranted.


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