Management of significant secondary genetic findings in an ophthalmic genetics clinic

Electrophysiology-Guided Genetic Characterisation Maximises Molecular Diagnosis in an Irish Paediatric Inherited Retinal Degeneration Population

“…In childhood-onset IRD, some phenotypes are specific for mutations in a single gene or a relatively small subset of genes, e.g., XLRS (RS1), LCA (including RPE65, CEP290, AILP1, RDH12, CRX and CRB1, among others), and CSNB (including NYX, TRPM1 and CACNA1F, among others) [53]. EP may be particularly helpful in refining the clinical diagnosis, thus narrowing the scope of the genetic spectrum of interest, e.g., 1., electronegative ERG in a male with macular retinoschisis suggests RS1 genotype, while, e.g., 2., CSNB can be categorised by EP subtypes (i.e., Riggs vs. Schubert-Bornschein types).…”

“…pNGS revealed additional findings in ocular-implicated genes in 33 patients with 15 patients having more than one additional variant identified (Supplementary Table S2); however, these variants were mainly ACMG class 3 (VUS) and did not correlate well with the clinical phenotype. As whole exome testing was not conducted, secondary findings (i.e., reportable non-retinal genes of significance to ongoing patient welfare) were not included in the analysis [52,53].…”

Clinical and Genetic Re-Evaluation of Inherited Retinal Degeneration Pedigrees following Initial Negative Findings on Panel-Based Next Generation Sequencing

“…As per WES, digital storage of WGS data from unresolved cases/pedigrees may allow virtual panel tests to be performed in the future and for new gene associations to be made. The added risk in 1st-tier WGS approaches is the workload required to process the output data, which may require artificial intelligence algorithms to create actionable clinical outcomes within a reasonable timeframe [42], and detection of significant secondary findings relevant to other body systems (e.g., cancer risk genes) [10,43]. However, recent data from the UK 100,000 genomes project showed >40% genetic diagnosis rate using 2nd-tier WGS for heritable ophthalmic disease with previously negative 1st-tier genetic testing (e.g., pNGS, WES); WGS addressed issues including non-coding/structural variants, mitochondrial DNA variants, and poor coverage by exon-based approaches [8,44].…”

“…The 'cost-effectiveness' of genetic testing for IRDs includes not only the direct costs of genetic sequencing but also the surrounding infrastructure (e.g., genetic counsellor, MDT meeting, molecular geneticist/scientist time/training, clinic use). The broader the scope of a test (e.g., WGS), the greater the yield of non-diagnostic (potentially misleading) findings, including secondary findings, which must be reported [10,16,43]. The expenditure of limited resources on the use and interpretation of 1st-tier WGS in a health service of limited size reduces the number of patients/pedigrees that can be served.…”

“…First-tier genetic testing of IRDs with panel-based next-generation sequencing (pNGS) has a diagnostic yield of ≈70-80% [4][5][6]. Whole exome/genome sequencing (WES/WGS) may detect further variants, resolving up to 79% of pedigrees [7,8]; however, this increased scope of sequencing comes with increased cost and requires resources to process and store data as well as effectively manage significant secondary findings [9,10].…”