A molecular diagnosis can be associated with medical actionability, informing clinical management of genetic disease, for example, by pointing to clinical guidelines for surveillance or to precision therapies. However, the rate of genetic test results that is medically actionable remains unknown in real-world clinical testing. Understanding the degree to which gene testing can inform medical care is important because it has broad relevance for clinical care, professional practice guidelines, patient advocacy, health economic research, and insurance reimbursement.
From May 2016 to May 2024, 86,767 unrelated probands had multigene panel testing (MGPT) for inborn errors of immunity (IEI) at a single commercial laboratory. Positive molecular diagnoses in this cohort were matched to expert-curated lists of genetic disorders with clinical management guidelines, which included ACMG secondary findings (PMID: 37347242), ClinGen actionability (PMID: 38757444), the rx-genes database (PMID: 33350578), and actionable disorders from newborn screening (PMID: 38585998). Actionable yield was calculated as the product of the diagnostic yield and the actionability rate. Results were stratified by clinician-reported race, ethnicity, or ancestry (REA) group. Additionally, the frequency of positive results was calculated for family members of probands diagnosed with actionable conditions who participated in cascade testing.
The diagnostic rate was 8.0% with 96.3% of those results being linked to medical actionability; thus, the overall actionable yield was 7.7%. Among patients with a molecular diagnosis, the rates of actionable results did not differ among REA groups overall. Finally, the rate of positive results in family members undergoing cascade testing for actionable disorders was 37.6%.
The majority of molecular diagnoses in MGPT for IEI conditions appeared to be associated with medical actionability, invoking opportunities for clinical care such as precision therapies, recommended surveillance, and other interventions. Our study suggests that in the setting of real-world clinical genetic testing, the gap between molecular diagnosis and medical actionability is surprisingly narrow. Our data highlight specific areas of medicine where research and professional practice guidelines are most needed to close the existing actionability gaps. Finally, these results underscore the potential high clinical utility of family cascade testing, which remains underutilized in clinical genetic testing.
