Clinical impact of whole-exome sequencing: 10 years of the Great Ormond Street Hospital Autoinflammation Centre of Excellence experience.

Abstract

To evaluate the diagnostic yield of whole-exome sequencing (WES) vs targeted gene panel (TGP) testing in patients evaluated for autoinflammation at the Great Ormond Street Hospital Autoinflammation Centre of Excellence. We retrospectively analysed 476 patients who underwent TGP testing between 2015 and 2022, and 210 patients who underwent WES between 2022 and 2025. Analysis of WES data combined: (i) a virtual gene panel of genes (germline and somatic) associated with inflammation; (ii) agnostic filtering according to ClinVar classification of pathogenicity; (iii) copy number variant analysis using ExomeDepth; and (iv) phenotype-driven prioritization using Exomiser. 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 the cases, including variants predisposing to cancer or cardiomyopathy. 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 will be an inevitable shift from WES to whole-genome sequencing in the future, significant challenges remain for WGS, including costly large-data handling and storage, and uncertainty about the interpretation of variants in non-exonic regions. Our findings, therefore, demonstrate the significant clinical impact of WES for the work-up of autoinflammation, with pragmatic utility for timely return of results.