Recommendations for returning genomic incidental findings? We need to talk!

Area of Science:

• Genomics
• Medical Genetics
• Clinical Sequencing

Background:

• The American College of Medical Genetics and Genomics (ACMG) issued recommendations for reporting incidental findings from clinical whole-genome sequencing (WGS) and whole-exome sequencing (WES).
• These recommendations mandate evaluating a specific gene set and reporting all pathogenic variants, regardless of patient age.
• The targeted genes are linked to highly penetrant disorders with available treatments or preventive measures.

Purpose of the Study:

• To critically evaluate the ACMG's recent recommendations on reporting incidental findings from WGS and WES.
• To highlight concerns regarding the recommendations, including opportunistic screening and lack of evidence for unselected populations.
• To advocate for a broader dialogue to establish evidence-based and normatively sound guidelines.

Main Methods:

• Review and analysis of the ACMG's published recommendations on incidental findings.
• Examination of the evidence base for predictive value, penetrance, phenotypes, and intervention efficacy for the recommended genes in unselected populations.
• Assessment of the ethical and professional consensus regarding patient consent and reporting of adult-onset findings in pediatric testing.

Main Results:

• The ACMG's recommendations promote opportunistic screening for actionable incidental findings.
• Significant gaps exist in evidence regarding the predictive value, penetrance, and intervention efficacy for many recommended genes in unselected populations.
• The recommendations conflict with patient autonomy by not allowing declination of incidental findings and with professional consensus on reporting adult-onset results in pediatric cases.

Conclusions:

• The ACMG's recommendations for incidental findings in WGS/WES are premature and raise significant concerns.
• There is a need for more robust evidence and a stakeholder dialogue to develop ethically sound and evidence-based guidelines.
• Current recommendations lack sufficient support regarding predictive value, patient consent, and consistency with established professional norms.