High number of candidate gene variants are identified as disease‐causing in a period of 4 years

Abstract

Advances in bioinformatic tools paired with the ongoing accumulation of genetic knowledge and periodic reanalysis of genomic sequencing data have led to an improvement in genetic diagnostic rates. Candidate gene variants (CGVs) identified during sequencing or on reanalysis but not yet implicated in human disease or associated with a phenotypically distinct condition are often not revisited, leading to missed diagnostic opportunities. Here, we revisited 33 such CGVs from our previously published study and determined that 16 of them are indeed disease‐causing (novel or phenotype expansion) since their identification. These results emphasize the need to focus on previously identified CGVs during sequencing or reanalysis and the importance of sharing that information with researchers around the world, including relevant functional analysis to establish disease causality.

Considerations for reporting variants in novel candidate genes identified during clinical genomic testing

“…Ultimately, facilitating gene discovery and the subsequent establishment of a new gene-disease relationship should improve diagnostic rates. For example, one clinical-research group recently reported 55 that among 33 candidate genes/variants identified by their program, 16 were established as pathogenic and explanatory in an average of under three years, 15/33 continued to be candidates, and only 2/33 were ultimately excluded from consideration, suggesting that the yield of “real” diagnoses from novel candidate genes is high. Finally, many large-scale clinical and hybrid clinical-research genomic testing efforts are already identifying, sharing, and reporting results in novel candidate genes and have described substantial benefits in identifying a genetic diagnosis for their patients.…”

“…Ultimately, facilitating gene discovery and the subsequent establishment of a new gene-disease relationship should improve diagnostic rates. For example, one clinicalresearch group recently reported55 that among 33 candidate genes/variants identified by their program, 16 were established as pathogenic and explanatory in an average of under three years, 15/33 continued to be candidates, and only 2/33 were ultimately excluded from consideration, suggesting that the yield of "real" diagnoses from novel candidate genes is high.…”