TOPLINE:

In patients with suspected autoinflammation, whole exome sequencing (WES) achieved a 19.5% diagnostic yield, compared with 14.9% with targeted gene panel testing for autoinflammatory disease testing, and WES also enabled the identification of incidental findings.

METHODOLOGY:

• Researchers retrospectively analyzed data of 476 patients who underwent targeted gene panel testing between 2015 and 2022 and of 210 patients who underwent WES between 2022 and 2025 at the Great Ormond Street Hospital Autoinflammation Centre of Excellence in London, England.
• Patients included for testing were suspected by their clinicians of having a genetic cause for their inflammatory phenotypes. The inflammatory phenotypes included recurrent fever, neuroinflammation, Behçet disease, systemic lupus erythematosus, systemic sclerosis, and others.
• Demographic and clinical data were collected using standardized forms. Human Phenotype Ontology terms were provided by clinicians to describe the phenotypes for patients who underwent WES, aiding in refining immunophenotypes. These data were not available for patients who underwent targeted gene panel testing.
• Patient DNA was either obtained directly or extracted from whole blood or saliva. The analysis of WES data combined virtual gene panel filtering and somatic variant filtering, copy number variant analysis, and phenotype-driven prioritization with relevant Human Phenotype Ontology terms. Targeted gene panel sequencing was performed using custom SureSelect panels.
• A multidisciplinary team manually reviewed the relevance of variants using various tools, and clinically actionable variants were recommended for validation through diagnostic laboratories. Participants provided informed written consent, including explicit consent for the reporting of incidental findings.

TAKEAWAY:

• Targeted gene panel testing identified molecular diagnoses in 14.9% of patients, and WES increased the molecular diagnostic yield to 19.5% of patients, with a 4.6% improvement over the targeted gene panel.
• In the WES cohort, 51 variants contributed to molecular diagnoses, and 27.5% of these would not have been detected if only the virtual panel workflow had been used.
• Among the 41 positive cases in the WES cohort, 40 unique pathogenic genotypes were identified, of which 70% were detected through multiple analysis arms, highlighting the benefit of a multipronged approach.
• Incidental findings were identified in 13.8% of patients who underwent WES, whereas systematic analysis for incidental findings was not included in the targeted gene panel framework.

IN PRACTICE:

“WES undoubtedly leads to increased diagnostic yield for multiple reasons, including increased numbers of genes compared to TGPs [targeted gene panels] and more sophisticated analytical approaches,” the authors wrote. “We recognize that WES is not available widely in routine clinical care, despite a narrowing of the gap in cost between TGP and WES. Therefore, we advocate for WES/[whole-genome sequencing] to be increasingly used in the future because the clinical impact may be significant,” they added.

SOURCE:

The study was led by Fiona Price-Kuehne, MBBS, and Alice Burleigh, PhD, University College London Great Ormond Street Institute of Child Health, London. Burleigh is now a postdoctoral research fellow at the University of Edinburgh in Edinburgh, Scotland. It was published online on January 29, 2026, in Rheumatology.

LIMITATIONS:

The findings may be affected by referral bias due to the focus on a specialized service in a UK-based cohort. WES incorporated copy number variant analysis but lacked sensitivity for detecting large chromosomal abnormalities and smaller copy number changes. The lower depth of coverage in WES compared with targeted gene panels could hinder the detection of low-level somatic mutations.

DISCLOSURES:

The study received funding from Great Ormond Street Hospital Children’s Charity, Rosetrees Trust, the National Institute of Health and Care Research Great Ormond Street Hospital Biomedical Research Centre, and Versus Arthritis. Two authors disclosed receiving institutional grants, and one of them declared receiving consultancy and speaker fees from various sources including Novartis, SOBI, and Roche.

This article was created using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication.