Re-evaluation and Re-analysis of 152 research exomes five years after the initial report reveals clinically relevant changes in 20%

Abstract

Iterative re-analysis of NGS results is not well investigated for published research cohorts of rare diseases. We revisited a cohort of 152 consanguineous families with developmental disorders (NDD) reported five years ago. We re-evaluated all reported variants according to diagnostic classification guidelines or our candidate gene scoring system (AutoCaSc) and systematically scored the validity of gene-disease associations. Sequencing data was re-processed using an up-to-date pipeline for case-level re-analysis. In 30/152 (20%) families, we identified a clinically relevant change. Thirteen previously reported (likely) pathogenic variants were re-classified as VUS/benign. In three cases, the gene-disease association (TSEN15, NAPB, and FAR1) validity was judged as limited. We identified 12 new disease causing variants. Two previously reported variants were missed by our updated pipeline due to alignment or reference issues. Our results support the need to re-evaluate screening studies, not only the negative cases but including supposedly solved ones. This also applies in a diagnostic setting. We highlight that the complexity of computational re-analysis for old data should be weighed against the decreasing re-testing costs. Since extensive re-analysis per case is beyond the resources of most institutions, we recommend a screening procedure that would quickly identify the majority (83%) of new variants.

Routine Diagnostics Confirm Novel Neurodevelopmental Disorders

“…In addition, the variant in NSMF turned out to be irrelevant, as a more convincing deletion of 41 genes could be identified in a subsequent analysis. While we in general recommend reporting rare or even unusual variants, these nine cases strongly highlight the need for regular re-evaluations in routine diagnostics, not only to confirm the proposed genetic cause communicated to the affected individual, but also to retract variants that turn out to be irrelevant [ 38 ]. There are several types of re-evaluations.…”

Clinical exome sequencing data from patients with inborn errors of immunity: cohort level meta-analysis and the benefit of systematic reanalysis

“…Second, the reanalysis strategy can implement additional sequencing, variant filtering or ancillary technologies to enhance the molecular diagnostic yield. ES-based resequencing with superior advancements in sequencing chemistry compared to outdated exome data can significantly upgrade data quality and is recommended by medical genetics guidelines (12,14,76,77). Moreover, the application of trio-ES has been shown to improve variant prioritization and interpretation, allowing for segregation and variant phasing in the affected proband and potentially affected family members (12,20,72,78,79).…”