Diagnostic impact of secondary findings from whole genome or whole exome sequencing in patients diagnosed with genetic eye disorders

Abstract Purpose Whole exome or genome sequencing (WES and WGS, respectively) can be valuable in identifying the molecular basis of inherited retinal disorders (IRD), particularly when panel-based testing yields negative or inconclusive results. However, WES or WGS may reveal secondary findings (SF) associated with severe diseases such as cancer, neurodegenerative and cardiovascular conditions. The American Society of Medical Genetics and Genomics has defined a list of reportable SFs that entail significant health implications. Acknowledging the limited awareness of SFs among ophthalmologists, we sought to understand the frequency, characteristics, and impact of SF following WES/WGS. Design Retrospective cross-sectional study Subjects, Participants and/or Controls We included patients with suspected IRD who underwent WES or WGS at Johns Hopkins Hospital from 2019-2024. WES/WGS was ordered following genetic counseling and consenting by certified genetic counselors (CGCs). Methods/ Main Outcome Measures We conducted a qualitative analysis of WES/WGS indications and SF. We also analyzed SF consent status and recommended clinical actions. Results The study included 36 patients, 50% of whom were females. 34 patients received WES, and two received WGS. The mean age was 45 ± 24 years. 89% (32/36) patients consented to examine SF, while 11% declined analysis. Of the 32 patients who consented to SF analysis, 5 had SFs (16%). Detected SF included pathogenic or likely pathogenic variants in the APC, RET, TP53, MUTYH, and BRCA2 genes associated with familial adenomatous polyposis, multiple endocrine neoplasia, Li-Fraumeni syndrome, MYH -associated polyposis, and hereditary breast and ovarian cancer, respectively. After WES/WGS, patients were advised to continue managing their symptoms with their healthcare team, take further medical actions, and/or encourage family members to pursue SF genetic testing. Of the 33 individuals who received post-test genetic counseling, 79% (26/33) were counseled by a CGC, 18% (6/33) by an ophthalmologist, and 3% (1/33) by a primary care provider. IRD gene results were positive in six (16%) patients, none of whom had SF. Conclusions SF are not infrequent when pursuing WES/WGS for diagnostic testing in IRDs. This study highlights the need for ophthalmologists to be prepared to discuss and manage SF. Multidisciplinary care, including a CGC, enables successful clinical management in this context.