O39: Genome x environment analysis of sudden unexpected infant death unveils etiologic heterogeneity and strong cannabis and genetic disease risks

Methods: We piloted a centralized, collaborative approach within the Undiagnosed Diseases Network (UDN) beginning in April 2025 by transferring an initial cohort of 382 participants from their original clinical sites to UDN Central, a multidisciplinary resource aimed to improve efficiencies, sustain diagnostic efforts, and streamline participant communication.UDN Central assumed management of genomic reinterpretation, clinical reanalysis, participant communication, and identification of appropriate additional research strategies for each case.UDN Central is composed of physicians, genetic counselors, and staff within the UDN partnering with patient navigators-whose team includes nurses, nurse practitioners, and social workers-within the patient-led 501(c)(3) the Undiagnosed Diseases Network Foundation (UDNF).Cases enter a consult workflow staffed by a genetic counselor (0.6 FTE) and additional clinicians, which then triages cases to the UDN Central Consultation Committee.There, clinicians from across the network and outside experts provide input on diagnostic possibilities.Case review order is determined based on original site prioritization, participant-reported clinical changes, systematic reinterpretation initiatives, and automated data alerts (eg, ClinVar classification updates).UDNF patient navigators serve as points of contact for all participant communications.To support communication, a standardized wrap-up documentation process was developed for communication with participants after completion of the consult workflow, summarizing the multidisciplinary review process and clinical recommendations.To pilot alternative workflows, selected cases were sent directly to domain-specific clinicians rather than through the established consult workflow, allowing for targeted evaluation of further diagnostic needs.In parallel to the consult workflow, systematic reinterpretation initiatives identified cases for the application of novel technologies (eg, long-read genome sequencing (GS)).Results: Of 382 cases transferred to UDN Central, 340 remained actively assigned after reassignment and withdrawal.Since transfer, 107 participants engaged with patient navigation services.From April to October 2025, 46 consultation requests were submitted, with 36 completed and results reported.Among these 36 cases, outcomes included 4 confirmed diagnoses (11.1%), 8 likely diagnostic variants under further evaluation (22.2%), 5 research variants requiring additional investigation (13.9%), and 4 clinical candidates without identified genetic etiology (11.1%).Fifteen cases (41.7%) remain undiagnosed, including 9 (25.0%)referred for specialist evaluation.Overall, 25 of 36 cases (69.4%) were reassigned to clinical sites for additional workup, while 11 (30.6%)remain under review at UDN Central.To facilitate access to emerging technologies for cases not already in the consult workflow, 63 cases were identified for long-read GS and patient navigators informed participants of next steps.Alternative strategies outside the consult workflow trialed for reviewing cases increased case throughput but introduced duplicated coordination, limiting potential efficiency gains.Conclusion: Systematic, longitudinal re-review through a centralized, multidisciplinary, patient-partnered framework can significantly advance diagnoses for individuals with rare and undiagnosed conditions and meets participants' needs for comprehensive evaluation and ongoing communication.Importantly, diagnostic insights arise not only from new data generation but also from renewed interpretation of existing findings.For example, multidisciplinary expert collaboration enabled rapid reassessment of a PBX1 variant previously considered non-diagnostic, underscoring the importance of expertise and cross-site resources in advancing rare disease diagnoses.Structured, multidisciplinary collaboration and ongoing reinterpretation improve diagnostic outcomes for individuals with rare and undiagnosed diseases.Ongoing multidisciplinary collaboration and continued investment in the UDN approach remain critical to advancing rare disease diagnosis.