CLINICAL IMPLICATIONS OF GENOME SEQUENCING IN THE DIAGNOSIS OF HEREDITARY DISEASES

Abstract

The study was a comparative diagnostic study that assessed the clinical utility of whole-genome sequencing as a first-line test in hereditary conditions in 1,250 people who had negative or inconclusive conventional genetic test results. Whole-genome sequencing has a diagnostic yield of 43.8 percent versus the cumulative yield of 27.4 percent of sequential whole-exome sequencing, chromosomal microarray, and targeted panel. Balanced structural variants, deep intronic variants, copy number variations, and mitochondrial mutations were the most significantly improved variants, this being a type of variant that the older methods often ignored. Sequential testing also dropped down to 13 days with whole-genome sequencing, a cut down of 398 days between sequential testing and the median time to diagnosis, a mind-boggling cut of the diagnostic process. Coverage uniformity analysis showed that whole-genome sequencing exhibited much less variation across GC-rich regions and repetitive elements compared to whole-exome sequencing, whereas the latter can better identify complex variants. Whole-genome sequencing reanalysis of data at 36 months provided an extra 12.8 percent diagnoses, almost twice the 7.5 percent of whole-exome sequencing reanalysis. The incremental cost-effectiveness ratio was estimated to be 9,247 per incremental diagnosis, and the whole-genome sequencing was deemed to dominate in a higher number of bootstrap replicates, 98 percent, which is a smaller price and increased functionality compared to sequential tests. The management of 94.5 percent of patients with the diagnosis changed, 39.9 percent of patients started on targeted therapy, and 34.6 percent of patients avoided invasive procedures initially planned. It demonstrates that first-line whole-genome sequencing is more diagnostic; has a lower turnaround time; has better variant detection; has a larger value of reanalysis; is more cost-effective; and has a greater clinical impact than the alternative molecular diagnostic test of suspected hereditary disorders in clinical practice.