Periodic reanalysis of whole-genome sequencing data enhances the diagnostic advantage over standard clinical genetic testing

Abstract

Whole-genome sequencing (WGS) as a first-tier diagnostic test could transform medical genetic assessments, but there are limited data regarding its clinical use. We previously showed that WGS could feasibly be deployed as a single molecular test capable of a higher diagnostic rate than current practices, in a prospectively recruited cohort of 100 children meeting criteria for chromosomal microarray analysis. In this study, we report on the added diagnostic yield with re-annotation and reanalysis of these WGS data ~2 years later. Explanatory variants have been discovered in seven (10.9%) of 64 previously undiagnosed cases, in emerging disease genes like HMGA2. No new genetic diagnoses were made by any other method in the interval period as part of ongoing clinical care. The results increase the cumulative diagnostic yield of WGS in the study cohort to 41%. This represents a greater than 5-fold increase over the chromosomal microarrays, and a greater than 3-fold increase over all the clinical genetic testing ordered in practice. These findings highlight periodic reanalysis as yet another advantage of genomic sequencing in heterogeneous disorders. We recommend reanalysis of an individual's genome-wide sequencing data every 1-2 years until diagnosis, or sooner if their phenotype evolves.

The genome empowerment scale: An assessment of parental empowerment in families with undiagnosed disease

“…[ES] and whole-genome sequencing [GS]) has yielded previously elusive diagnoses in~40% of refractory phenotypes and has also allowed the discovery of new ultra-rare diseases. 1,2 With the increasing availability and decreasing costs, ES is now a first or second tier test in clinical genetics practice [3][4][5] and GS will soon be more widely available for clinical practice.…”

Systematic re-annotation of 191 genes associated with early-onset epilepsy unmasks de novo variants linked to Dravet syndrome in novel SCN1A exons

“…This study further raises the question whether it would be more desirable to use WGS for diagnostic purposes, as data can be iteratively re-annotated when updated annotation information becomes available. Similarly, this approach has already been proven successful as iteratively re-analyzing patient genomes when new causative genes are discovered increases diagnostic yield 6,38 .…”

Ethical considerations for modern molecular pathology

“…Genetic alterations of which the clinical significance is still unclear today may be classified in the future as definitely pathogenic or benign. The possibility of reanalysis is a big advantage of DNA sequencing, maximizing its benefit for clinical care . Current literature on (whether, and to what extent there is an obligation for) genetic reanalysis is focused on the CG context using WES/WGS.…”

“…benefit for clinical care [68,69] . Current literature on (whether, and to what extent there is an obligation for) genetic reanalysis is focused on the CG context using WES/WGS.…”

“…The question, then, is whether laboratories should (systematically) reanalyze stored genetic data. For the CG context, periodic reanalysis has been recommended in nondiagnostic cases, although a recent interdisciplinary working group came to the consensus that laboratories have no obligation to routinely analyze data [68,70,73,74]. In the MP context, laboratories are encouraged to set up clear and appropriate policies, but discussion in literature, let alone consensus in the MP context, are lacking on what would be an appropriate reanalysis and recontact policy [10,23,[75][76][77][78].…”