Global Collaboration in Rare Disease Research: The Story of the International Replication Repair Deficiency Consortium

Alessandro Mannucci, MD, CGA-IGC Communications Committee Member

In the final episode of our research collaboration podcast series, CGA-IGC's Emma Keel, a genetic counselor at the University of Chicago, sits down with Melyssa Aronson and Lucie Stengs from Toronto’s Hospital for Sick Children to discuss the evolution and global impact of the International Replication Repair Deficiency Consortium (IRRDC)—a major collaborative effort to understand and manage constitutional mismatch repair deficiency (CMMRD) and related syndromes.

Origins in Toronto

The IRRDC began as a local initiative in the early 2000s. It emerged from collaborations between Zane Cohen Centre for Digestive Diseases, at Mount Sinai Hospital, and the neuro-oncology team at SickKids. Initially driven by the clinical overlap between GI polyposis syndromes and pediatric brain tumors, the teams joined forces to collect biospecimens and clinical data on rare CMMRD cases. As the registry grew in scope and complexity, operations shifted to SickKids, where resources for international coordination and biobanking could better support a global mission.

From A Registry to Consortium

Under the leadership of Dr. Uri Tabori, the IRRDC consortium has grown into a hub for both diagnostic innovation and therapeutic guidance in CMMRD. The SickKids team now manages a globally-scaled biobank and research database, with clinical input from collaborators across North America, the Middle East, and South Asia.

The consortium collects tumor and blood samples from affected individuals, often coordinating international shipments and ensuring that data and biospecimens are stored and processed under ethically approved protocols. The team also developed functional assays to help resolve diagnostic uncertainties, such as variants of unknown significance (VUS) in MMR genes — an invaluable resource for clinicians who need to manage patients with VUS results.

Global Collaboration and Impact

What began as a five-family cohort has evolved into a widely recognized international research infrastructure. Key to this growth has been the consortium’s openness to collaboration, equitable authorship practices, and support for partner sites through diagnostic testing, therapeutic insights, and logistical assistance.

International symposia, strategic conference presentations, and word-of-mouth referrals all contributed to the consortium growth, fueled international interest, and expanded partnerships. The ability to offer functional testing and guidance on immunotherapy access has made the IRRDC an essential ally for clinicians managing complex pediatric patients with cancers in resource-constrained settings.

Infrastructure, Funding, and Oversight

Running a biobank of this scale requires substantial coordination and support. The consortium is backed by a combination of philanthropic foundations—including the Meagan Bebenek Foundation, LivWise Foundation, and Harry Agganis Foundation—and large-scale research grants. Administrative oversight involves managing multiple IRB protocols, data use agreements, and frequent ethical reviews to ensure alignment with patient autonomy and international standards. Crucially, the IRRDC integrates patient advocacy input into its governance, underscoring its commitment to ethically grounded, patient-centered research.

A Model for Rare Disease Research

The IRRDC showcases how multidisciplinary and international cooperation can advance understanding and care in ultra-rare genetic conditions. By bridging clinical, research, and logistical aspects, the consortium has established a replicable model for addressing the global challenges of rare disease research—while directly benefiting families who would otherwise lack access to expert guidance and advanced diagnostics.

 If you have any questions or are interested in joining the consortium please contact or Melyssa Aronson (melyssa.aronson@sinaihealth.ca) or Lucie Stengs (lucie.stengs@sickkids.ca).  

For more details on the IRRDC, the consortium’s recent publication in Lancet Oncology (Logine Negm, et al. Lancet Oncol 2025; 26 (1): 123-135)

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If you enjoyed this podcast, you may like the first two podcasts of the CGA-IGC Research Collaboration series- the LINEAGE Consortium, and the GASTRIC Consortium or others from the CGA-IGC Podcast Series (Seasons 3, 4, 5, 6 & 7) presented by the CGA-IGC Education Committee. Or, explore our Expert Approach to Hereditary Gastrointestinal Cancers podcast series (Seasons 1 and 2). We're also on Spotify!

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