Pharmacotherapy Risks in Rare Genetic Diseases: Cross‐Referencing ACMG Secondary Findings v3.2 List With Clinical Databases

Clinical genomics and pharmacogenomics have largely remained separate fields, though some genetic variants have overlapping disease risk and drug implications. However, the extent of this overlap is not well studied. To explore this gap, we cross-referenced genes from the American College of Medical Genetics Secondary Findings v3.2 list with genomic databases and drug labeling to identify gene-phenotype pairs with overlapping clinical genomics and pharmacogenomic implications. We searched GeneReviews and PharmGKB (now called ClinPGx) for each gene-phenotype pair and reviewed the FDALabel database contraindications or warnings. Targeted therapies for specific germline/somatic variants were excluded. PGx-trained pharmacists and a genetic counselor classified gene-phenotype pairs into three levels: Level 1 (Food and Drug Administration's or guideline-driven recommendations), Level 2 (potential pharmacotherapy implication), and Level 3 (no/weak interactions). Among 97 gene-phenotype pairs reviewed, 22 (23%) were Level 1, 31 (32%) were Level 2, and 44 (45%) were Level 3. Pharmacotherapy implications included risks inferred by disease pathology (e.g., anticoagulants and hereditary hemorrhagic telangiectasia) and less obvious associations (e.g., Marfan syndrome and fluoroquinolones). Unrecognized medication implications may pose patient safety risks. Greater research, information consolidation and dissemination, and multidisciplinary collaboration among clinical genomics specialists, pharmacogenomic specialists, and other practitioners are essential as genetic testing becomes routine in clinical care.