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

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  1 , Julie P Taylor  1 , Revathi Rajkumar  1 , Krista Bluske  1 , Maren Bennett  1 , Laura M Amendola  1 ; ICSL Interpretation and Reporting Team; David R Bentley  1 , Ryan J Taft  1 , Denise L Perry  1 , Alison J Coffey  1
Collaborators, Affiliations

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 et al. Cell Genom. .

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.

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Conflict of interest statement

All authors are employees and shareholders of Illumina, Inc.

Figures

None
Graphical abstract
Figure 1
Figure 1
Reactive gene curation supports a cGS test for RUGDs (A) Flow diagram outlining the incorporation of reactive gene curation into ICSL’s clinical interpretation and reporting workflow. (B) Percentage of cases for which gene curation was required. (C) Percentage of cases requiring gene curation as a function of time relative to the first analyzed case (blue) compared with the growth in GDR classifications publicly available through ClinGen (orange).
Figure 2
Figure 2
Evidence supporting GDRs for rare disease (A) Points awarded to genetic and experimental evidence across the 274 curated GDRs with a classification of limited and above. Each row represents a single GDR. Dashed vertical lines show the boundary between limited and moderate (7 pts) and moderate and strong/definitive (12 pts). (B) Percentage of GDRs for which animal models were curated and scored. (C) Number of curated models plotted according to the degree of phenotype recapitulation and species. (D) Percentage of GDRs for which segregation evidence was curated and scored. (E) Percentage of GDRs for which a cohort study organized through GeneMatcher was curated.
Figure 3
Figure 3
Reactive gene curation supports clinical reporting for a cGS test for RUGDs (A) Use of GDR classification in variant classification and reporting. (B) Categorization of GDRs for clinical reporting as a percentage of total GDRs curated. The GDR classified as disputed is not depicted. (C) Number of curated GDRs within each gene-disease validity classification. (D) Number of variants reported for curated GDRs, stratified according to variant and GDR classification. ∗Variant reported as P for moderate GDR based on clinical judgment. (E) Recurrent GDRs for which variants were reported in multiple unrelated probands.
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