Consultation Informs Strategies to Improve Functional Evidence Use in Variant Classification

Overview

Journal medRxiv

Date 2024 Dec 16

PMID 39677445

Authors

Rehan M Villani

Bronwyn Terrill

Emma Tudini

Maddison E McKenzie

Corrina C Cliffe

Christopher N Hahn

Ben Lundie

Tessa Mattiske

Ebony Matotek

Abbye E McEwen

Sarah L Nickerson

James Breen

Douglas M Fowler

John Christodoulou

Lea Starita

Alan F Rubin

Amanda B Spurdle

Affiliations

Soon will be listed here.

Abstract

To determine if a variant identified by diagnostic genetic testing is causal for disease, applied genetics professionals evaluate all available evidence to assign a clinical classification. Experimental assay data can provide strong functional evidence for or against pathogenicity in variant classification, but appears to be underutilised. We surveyed genetic diagnostic professionals in Australasia to assess their application of functional evidence in clinical practice. Results indicated that survey respondents are not confident to apply functional evidence, mainly due to uncertainty around practice recommendations. Respondents also identified need for support resources, educational opportunities, and in particular requested expert recommendations and updated practice guidelines to improve translation of experimental data to curation evidence. As an initial step, we have collated a list of functional assays recommended by 19 ClinGen Variant Curation Expert Panels as a source of international expert opinion on functional evidence evaluation. Additional support resources for diagnostic practice are in development.

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