Reactive gene curation to support interpretation and reporting of a clinical genome test for rare disease: Experience from over 1,000 cases

Amanda R Clause; Julie P Taylor; Revathi Rajkumar; Krista Bluske; Maren Bennett; Laura M Amendola; ICSL Interpretation and Reporting Team; David R Bentley; Ryan J Taft; Denise L Perry; Alison J Coffey

doi:10.1016/j.xgen.2023.100258

Reactive gene curation to support interpretation and reporting of a clinical genome test for rare disease: Experience from over 1,000 cases

Cell Genom. 2023 Jan 31;3(2):100258. doi: 10.1016/j.xgen.2023.100258. eCollection 2023 Feb 8.

Collaborators

ICSL Interpretation and Reporting Team:
Carolyn Brown, Matthew P Brown, Amanda Buchanan, Brendan Burns, Nicole J Burns, Anjana Chandrasekhar, Aditi Chawla, Katie Golden-Grant, Akanchha Kesari, Alka Malhotra, Becky Milewski, Samin A Sajan, Zinayida Schlachetzki, Sarah Schmidt, Brittany Thomas, Erin Thorpe

Affiliation

¹ Medical Genomics Research, Illumina, Inc., San Diego, CA 92122, USA.

Abstract

Current standards in clinical genetics recognize the need to establish the validity of gene-disease relationships as a first step in the interpretation of sequence variants. We describe our experience incorporating the ClinGen Gene-Disease Clinical Validity framework in our interpretation and reporting workflow for a clinical genome sequencing (cGS) test for individuals with rare and undiagnosed genetic diseases. This "reactive" gene curation is completed upon identification of candidate variants during active case analysis and within the test turn-around time by focusing on the most impactful evidence and taking advantage of the broad applicability of the framework to cover a wide range of disease areas. We demonstrate that reactive gene curation can be successfully implemented in support of cGS in a clinical laboratory environment, enabling robust clinical decision making and allowing all variants to be fully and appropriately considered and their clinical significance confidently interpreted.

Keywords: ClinGen; GDR; RUGD; candidate gene; disease gene; gene curation; gene discovery; gene-disease relationship; genome sequencing; rare disease.