GA4GH Connect session follow up - Scaling the Federated Variant-Level Matching Network

[Beatrice Amos]

Dear Colleagues,

Thank you all for contributing to the GA4GH Connect session: Scaling the Federated Variant-Level Matching Network - what a productive and engaging discussion! A big thank you to Heidi Rehm, Nara Sobreira, Alex Wagner, and Larry Babb for an excellent session, and to all participants for their valuable contributions and engaging discussions. Your input made this a truly meaningful conversation.

‼️ Please take a moment to review the meeting notes and share any edits or additions to help keep the summary accurate and complete. If you notice any mistakes, have resources to add, or want to share more details, please feel free to jump in and update the notes - we welcome your input! A link to the recording is available in the linked meeting notes.

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Key Takeaways

🔶 Data sharing via VLM significantly reduces VUS rates by enabling variant reclassification, but requires balancing openness with authentication to prevent misuse, like by AI companies.
🔶 Standardisation and flexible implementations are crucial for scaling VLM networks inclusively, especially for under-resourced or regulated entities like clinical labs in low-income countries.
🔶 While research databases are connecting successfully, engaging commercial/clinical labs demands proving tangible benefits and addressing burdens like email overload and proprietary concerns through phased, reciprocal sharing.

 

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Meeting Summary

The meeting focused on advancing Variant Level Matching (VLM) to address challenges in rare disease genetics, such as high rates of Variants of Uncertain Significance (VUS) and the rarity of variants and genes, emphasising the need for global data sharing to enable gene discovery and variant interpretation.

Heidi Rehm introduced the VLM system, highlighting implementations in databases like Variant Matcher, Franklin, Seqr, and Geno2MP, connected viaBeacon V2 API and Auth0 for authentication, with examples of successful gene discoveries and variant reclassifications.
Alex Wagner discussed the Variation Representation Specification (VRS) and the AnyVar tool to standardise variant representation, facilitate liftover between genome builds, and create off-the-shelf solutions for ad hoc VLM networks, including loading Gregor Consortium data.
Nara Sobreira shared pilots with clinical labs in Brazil, demonstrating how VLM aids in reclassifying VUS, while addressing barriers like proprietary data concerns, regulatory issues, and the need for flexible sharing levels.

Discussions covered technical challenges like indel representation, phenotype granularity, duplicate data handling, and creating Beacon profiles, with a focus on scaling the network inclusively across research, clinical, and patient-led groups.

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Action Items

🔶 Develop and finalise technical documentation for joining the VLM network, including a guide on endpoints, expectations, and a Beacon V2 profile to lower barriers for new nodes.
🔶 Implement next-phase features like returning direct contact emails, detailed phenotypes (e.g. HPO terms, ICD/OMIM codes), affected status, and variant type queries per gene/region, while addressing indel and structural variant representation using tools like VRS.
🔶 Fix identified bugs (e.g. liftover issues in Seqr) and integrate more nodes to expand the network.
🔶 Explore genomic tags or decentralised persistent identifiers to handle duplicate datasets and identify matching individuals without excessive emails.
🔶 Continue pilots with clinical and patient-led groups to demonstrate value, refine consent/regulatory approaches, and ensure flexibility for varying sharing capabilities.

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Your feedback is invaluable and helps us improve future GA4GH Plenary and Connect meetings, ensuring they continue to provide the best possible experience for our community.

 If there's anything we missed or anything you'd like to add, feel free to reach out!

Thanks again for your engagement and contributions!

Best,
Beatrice

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Beatrice Amos

Work Stream Manager

beatri...@ga4gh.org

ba...@sanger.ac.uk

https://www.ga4gh.org/what-we-do/calendar/

[Beatrice Amos]

And here is the link to the meeting notes: https://docs.google.com/document/d/1faN6VnBL2VlEEQCGsnoIkTLYbd-7q-cEkJrjlYVPwE4

Best,

Beatrice