Framework for Evaluation and Reporting of Incidental Findings in Clinical Genome Sequencing

Research Background

In current clinical practice, clinical genome sequencing (CGS) is gradually becoming an important means for diagnosing rare genetic diseases. However, incidental findings (IFs) are often encountered in genome sequencing, which are unexpected results unrelated to the purpose of the test. Due to the lack of universally accepted guidelines for returning IFs, reporting policies for IFs are inconsistent and lack transparency. Therefore, researchers have developed a new framework to guide the evaluation and return of IFs encountered during CGS. This framework focuses on the clinical significance and actionability of IFs and proposes a step-by-step approach with stopping points to recommend whether to return IFs.

Paper Source

This paper was jointly completed by Carolyn M. Brown, Laura M. Amendola, Anjana Chandrasekhar, and other researchers from Illumina Laboratory Services (ILS), San Diego, a CAP-accredited and CLIA-certified clinical laboratory. The paper was published in the “European Journal of Human Genetics” in 2024 and was released online on April 2, 2024.

Research Process

Framework Development

An internal working group was first established, consisting of two clinical genomic scientists, two genetic counselors, and a laboratory director, who began meeting weekly in 2019. A survey of collaborating clinicians was conducted to assess their views on IFs. Based on the survey results, literature review, and recommendations from professional organizations, thresholds for clinical significance and actionability were determined. The framework prototype was compared with previous workflow decisions to ensure the clinical reasonableness of reporting decisions.

CGS Testing

The researchers performed CGS on collected DNA samples using Illumina sequencing technology for next-generation sequencing. Data processing included read alignment, variant detection, annotation, and comprehensive variant screening. The test could detect single nucleotide variants (SNVs), small insertion and deletion events, copy number variations (CNVs), and more.

Results

Between January 2021 and June 2022, 720 patients underwent CGS. During this period, 38 IFs were returned in 37 patients, covering 19 unique genes. The most common types of diseases involved in these IFs included blood disorders, cancer susceptibility, heart disease, and kidney disease. Implementation of the framework resulted in about 5.1% of patients receiving actionable IFs, which decreased to 3.1% when excluding glucose-6-phosphate dehydrogenase (G6PD) deficiency.

Research Conclusions

The implementation of this framework has brought consistency and transparency to the clinical reporting of IFs, addressing a key need in the genomics field and serving as a model for standardized evaluation and reporting of IFs.

Research Highlights

The highlights of this study include: the proposed framework increases the consistency of reporting decisions; the gene-agnostic approach of the framework may also increase the equity of types of IFs identified and returned across different patient populations; and the framework is also consistent with IF return decisions by other groups, being actionable for many genes reported in the literature or subsequently considered medically actionable genes in the ACMG list.

Research Limitations

The limitations of this study lie in the fact that provider-reported preferences for IF return may not be representative, given a response rate of less than 25%. Additionally, the expression of relevant information for sprint genes may be limited.