Reanalysis of Genomic Sequencing Results in a Clinical Laboratory: Advantages and Limitations

Abstract

Genetic diagnosis of patients with neurodevelopmental disorders is imperative and a standard clinical practice. Considering the continuous accumulation of data on disease-causing variants, reanalysis of previously established sequencing data is important. Periodic reanalysis of variants with uncertain significance has become mandatory in clinical laboratories. Therefore, to confirm the utility of the reanalysis of targeted gene panel data in clinical laboratories, we re-evaluated the data of two groups of patients who had undergone targeted gene panel testing for neurodevelopmental disorders (n = 116) and epileptic encephalopathy (n = 384). This reanalysis was based on a reannotation process reflecting updated databases. Six (5.2%) and seven (1.8%) new pathogenic or likely pathogenic variants were identified in these two groups, respectively, attributable to the updated guidelines and de novo reports from unrelated patients. Although relatively low, considerable increase in the diagnostic yield was confirmed. We suggest that reanalysis of genetic variants, mainly using changes in databases and updated interpretations, should be implemented as a routine practice in clinical laboratories.

Diagnostic performance of automated, streamlined, daily updated exome analysis in patients with neurodevelopmental delay

“…A variety of reasons for the improved diagnostic yield obtained by reanalysis have been reported, including new gene–disease associations and literature updates, updated and clarified patient phenotypes, additional sequencing for trios/other affected individuals and family members, improvements in sequencing data by resequencing strategies, upgraded bioinformatics tools, and research collaborations (Liu et al 2019 ; Fung et al 2020 ; Won et al 2020 ). The main reason for obtaining additional diagnoses by reanalysis has been attributed to the discovery of new gene-disease associations (Liu et al 2019 ; Fung et al 2020 ).…”

Updated Stroke Gene Panels: Rapid evolution of knowledge on monogenic causes of stroke

“…As has been suggested for other disorders, the diagnostic yield of WES and WGS tests of stroke patients may increase if data are regularly re-evaluated and the gene panels are updated [8, 15,16] and used in combination with recent detailed information on the phenotype.…”

Intellectual disability genomics: current state, pitfalls and future challenges

“…ID diagnosis strategy should also include systematic reanalysis of previously generated data, in light of the new knowledge [ 193 , 194 ], e.g. databases update, novel disease genes identification, new clinical features and molecular information [ 195 ]. This is a clear advantage of the ES / GS over the TNGS.…”