Abstract Objective To evaluate the diagnostic yield of whole exome sequencing (WES) vs targeted gene panel (TGP) testing in patients evaluated for autoinflammation at Great Ormond Street Hospital Autoinflammation Centre of Excellence. Methods We retrospectively analysed 476 patients who underwent TGP testing between 2015–2022; and 210 patients who underwent WES between 2022–2025. Analysis of WES data combined: 1. a virtual gene panel of genes (germline and somatic) associated with inflammation; 2. agnostic filtering according to ClinVar classification of pathogenicity; 3. copy number variant analysis using ExomeDepth; and 4. phenotype-driven prioritisation using Exomiser. Results TGP testing identified molecular diagnoses in 71/476 patients (14.9%). WES increased the molecular diagnostic yield to 41/210 patients (19.5%). WES also enabled the discovery of novel genotype-phenotype associations. Significant incidental findings were identified in 29/210 (13.8%) of cases, including variants predisposing to cancer or cardiomyopathy. Conclusion In patients with suspected autoinflammation, WES increased diagnostic yield compared with TGP testing while providing additional clinical value through novel gene discovery and capacity for future systematic reanalysis of unsolved cases. Incidental findings required careful and explicit a priori patient counselling and informed consent before offering WES. While there is an inevitable shift to whole genome sequencing, significant challenges remain, including costly large-data handling and storage, and uncertainty about the interpretation of variants in non-exonic regions. Our findings, therefore, demonstrate significant clinical impact of WES for the workup of autoinflammation, with pragmatic utility for timely return of results.
Price-Kuehne et al. (Fri,) studied this question.