Genomic Research as a Critical Pathway to Diagnosis for Individuals with Rare Disease
- 1Broad Institute of MIT and Harvard; Boston Children's Hospital and Harvard Medical School; Massachusetts General Hospital; Harvard Medical School
Abstract
Many individuals with rare monogenic disease remain molecularly undiagnosed due to challenges accessing genetic testing, ambiguity in interpretation of uncertain variants, and latency between novel disease-gene discovery and adoption into clinical pipelines. The Rare Genomes Project (RGP) provides a remote, research-based genomic sequencing (GS) service for rare disease families to overcome diagnostic barriers while advancing the understanding of the genetic basis of rare disease. Short-read GS and family-centered analysis were performed to identify causes of primary disease. Variants meeting return criteria were clinically confirmed and returned to families. Since 2017, RGP enrolled clinically heterogeneous, undiagnosed rare disease families from all fifty states, Washington DC, and Puerto Rico. Findings were returned to 272 of 1014 sequenced families, resulting in a solve rate of 23.3% and a returned strong candidate rate of 3.5%. Condition-specific return rates ranged from 15% to 40% with many families receiving a result in a known disease gene after healthcare access challenges. Research interventions contributed to returns in 16% of all families and included variants in recently discovered or non-coding disease genes, additional functional studies to resolve variant uncertainty, and real-time data sharing to empower novel disease-gene discovery. RGP demonstrates that a research-based, patient-driven remote sequencing study can effectively bridge a diagnostic gap for rare disease families underserved in current clinical care. This study also underscores the clinical utility of GS with frequent re-analysis and highlights the critical continued role of research in variant interpretation, method innovation, and genomic knowledge base expansion for rare disease diagnosis.
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BibTeX
@misc{odonnellluria2026genomic,
title = {{Genomic Research as a Critical Pathway to Diagnosis for Individuals with Rare Disease}},
author = {A. O'Donnell-Luria and S. DiTroia and M. C. OLeary and L. Pais and V. S. Ganesh and G. Lemire and E. OHeir and A. Neale and A. Pham and G. E. VanNoy and B. E. Mangilog and M. Singer-Berk and A. Sanchis-Juan and H. Snow and S. Abouhala and S. Agu and M. Amin and S. M. Baxter and B. Blankenmeister and K. M. Bujakowska and C. M. Carlston and S. Choufani and L. E. Covill and E. M. England and C. Glaze and J. Goodrich and E. Groopman and K. Laricchia and A. Kern Lovgren and J. Ma and E. Martinez and C. Mighton and B. OLeary and I. A. Osei-Owusu and S. Pajusalu and L. Romo and K. Russell and R. Sangermano and E. Seaby and J. Serrano and G. Shah and M. Singh and K. M. Socarras and Ste},
howpublished = {medRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.15.26363084},
url = {https://www.medrxiv.org/content/10.64898/2026.09.15.26363084v1},
note = {CC BY},
}
RIS
TY - UNPB
TI - Genomic Research as a Critical Pathway to Diagnosis for Individuals with Rare Disease
AU - A. O'Donnell-Luria
AU - S. DiTroia
AU - M. C. OLeary
AU - L. Pais
AU - V. S. Ganesh
AU - G. Lemire
AU - E. OHeir
AU - A. Neale
AU - A. Pham
AU - G. E. VanNoy
AU - B. E. Mangilog
AU - M. Singer-Berk
AU - A. Sanchis-Juan
AU - H. Snow
AU - S. Abouhala
AU - S. Agu
AU - M. Amin
AU - S. M. Baxter
AU - B. Blankenmeister
AU - K. M. Bujakowska
AU - C. M. Carlston
AU - S. Choufani
AU - L. E. Covill
AU - E. M. England
AU - C. Glaze
AU - J. Goodrich
AU - E. Groopman
AU - K. Laricchia
AU - A. Kern Lovgren
AU - J. Ma
AU - E. Martinez
AU - C. Mighton
AU - B. OLeary
AU - I. A. Osei-Owusu
AU - S. Pajusalu
AU - L. Romo
AU - K. Russell
AU - R. Sangermano
AU - E. Seaby
AU - J. Serrano
AU - G. Shah
AU - M. Singh
AU - K. M. Socarras
AU - Ste
PY - 2026
DA - 2026/09/15
PB - medRxiv
DO - 10.64898/2026.09.15.26363084
UR - https://www.medrxiv.org/content/10.64898/2026.09.15.26363084v1
AB - Many individuals with rare monogenic disease remain molecularly undiagnosed due to challenges accessing genetic testing, ambiguity in interpretation of uncertain variants, and latency between novel disease-gene discovery and adoption into clinical pipelines. The Rare Genomes Project (RGP) provides a remote, research-based genomic sequencing (GS) service for rare disease families to overcome diagnostic barriers while advancing the understanding of the genetic basis of rare disease. Short-read GS and family-centered analysis were performed to identify causes of primary disease. Variants meeting return criteria were clinically confirmed and returned to families. Since 2017, RGP enrolled clinically heterogeneous, undiagnosed rare disease families from all fifty states, Washington DC, and Puerto Rico. Findings were returned to 272 of 1014 sequenced families, resulting in a solve rate of 23.3% and a returned strong candidate rate of 3.5%. Condition-specific return rates ranged from 15% to 40% with many families receiving a result in a known disease gene after healthcare access challenges. Research interventions contributed to returns in 16% of all families and included variants in recently discovered or non-coding disease genes, additional functional studies to resolve variant uncertainty, and real-time data sharing to empower novel disease-gene discovery. RGP demonstrates that a research-based, patient-driven remote sequencing study can effectively bridge a diagnostic gap for rare disease families underserved in current clinical care. This study also underscores the clinical utility of GS with frequent re-analysis and highlights the critical continued role of research in variant interpretation, method innovation, and genomic knowledge base expansion for rare disease diagnosis.
ER -