Measuring disease likelihood in genomic ascertainment.

Area of Science:

• Genomics
• Medical Genetics
• Clinical Diagnostics

Background:

• Secondary findings from genetic testing require evaluation for clinical utility and policy development.
• The American College of Medical Genetics and Genomics (ACMG) Secondary Findings guidelines are applied across diverse testing scenarios.

Purpose of the Study:

• To assess the diagnostic yield, predictive power, and utility of secondary findings in a diverse participant cohort.
• To develop a quantitative method for evaluating the likelihood of a valid diagnosis for secondary findings.

Main Methods:

• Recruited participants from multiple sources for genetic testing analysis.
• Conducted genotyping, cascade testing, and phenotyping for 163 probands and their families.
• Developed and applied a method to estimate the likelihood of a valid clinicomolecular diagnosis for secondary findings, focusing on BRCA1/BRCA2 variants.

Main Results:

• Diagnostic yield of secondary findings showed high variability among families.
• For 59 families with BRCA1/BRCA2 secondary findings, the likelihood of a valid diagnosis ranged from 26.2% to 100%.
• 51% of families met criteria for diagnostic testing, indicating underutilization and potential inappropriate application of secondary findings analysis.

Conclusions:

• Secondary findings analysis in genetic testing has variable diagnostic utility.
• Current application of secondary findings testing may be inappropriate, with diagnostic testing for certain conditions being underused.
• Findings support policy refinement for secondary findings and inform discussions on population genomic screening.