Identifying Putative Pathogenic Non-Coding Variants in Unresolved Rare Disease Patients Using Topologically Associated Domains
- 1Division of Genetics and Genomic Medicine, Children's Hospital of Philadelphia
Abstract
Unresolved rare disease is a major public health challenge affecting ∼300 million people worldwide. At least 50% of these individuals remain genetically unresolved after applying exome sequencing and/or whole genome sequencing. One source of these missing diagnoses is the presence of rare variants within the non-coding genome that are detected but not interpreted by whole genome sequencing. In order to systematically evaluate candidate pathogenic non-coding variants, we created the G enomic A nalysis of V ariants in U nresolved R are D isease (GAVURD) system. GAVURD leverages trio whole genome sequencing alignment data to produce a short list of putative pathogenic non-coding variants for a given proband. GAVURD uses best practices for de novo and rare inherited variant identification, links variants to human disease genes harnessing topologically associated domain (TAD) data, and rank prioritizes variants based on phenotypic overlap. As a proof-of-concept, we applied GAVURD to ten probands with unresolved rare disease and implicated six potentially causal non-coding variants based on a confluence of evidence supportive of pathogenicity. The GAVURD system serves an important role in prioritizing candidate non-coding causal variants for unresolved rare disease that can serve as the high value and informed focus of additional functional follow-up studies.
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BibTeX
@misc{gacita2026identifying,
title = {{Identifying Putative Pathogenic Non-Coding Variants in Unresolved Rare Disease Patients Using Topologically Associated Domains}},
author = {A. M. Gacita and M. Pahl and M. D. Torres and S. Ganesan and J. J. Blair and K. Patel and R. Ramakrishnan and L. Conlin and I. Helbig and S. F. A. Grant},
howpublished = {bioRxiv},
year = {2026},
month = sep,
doi = {10.64898/2026.09.17.752339},
url = {https://www.biorxiv.org/content/10.64898/2026.09.17.752339v1},
note = {Public domain},
}
RIS
TY - UNPB
TI - Identifying Putative Pathogenic Non-Coding Variants in Unresolved Rare Disease Patients Using Topologically Associated Domains
AU - A. M. Gacita
AU - M. Pahl
AU - M. D. Torres
AU - S. Ganesan
AU - J. J. Blair
AU - K. Patel
AU - R. Ramakrishnan
AU - L. Conlin
AU - I. Helbig
AU - S. F. A. Grant
PY - 2026
DA - 2026/09/17
PB - bioRxiv
DO - 10.64898/2026.09.17.752339
UR - https://www.biorxiv.org/content/10.64898/2026.09.17.752339v1
AB - Unresolved rare disease is a major public health challenge affecting ∼300 million people worldwide. At least 50% of these individuals remain genetically unresolved after applying exome sequencing and/or whole genome sequencing. One source of these missing diagnoses is the presence of rare variants within the non-coding genome that are detected but not interpreted by whole genome sequencing. In order to systematically evaluate candidate pathogenic non-coding variants, we created the G enomic A nalysis of V ariants in U nresolved R are D isease (GAVURD) system. GAVURD leverages trio whole genome sequencing alignment data to produce a short list of putative pathogenic non-coding variants for a given proband. GAVURD uses best practices for de novo and rare inherited variant identification, links variants to human disease genes harnessing topologically associated domain (TAD) data, and rank prioritizes variants based on phenotypic overlap. As a proof-of-concept, we applied GAVURD to ten probands with unresolved rare disease and implicated six potentially causal non-coding variants based on a confluence of evidence supportive of pathogenicity. The GAVURD system serves an important role in prioritizing candidate non-coding causal variants for unresolved rare disease that can serve as the high value and informed focus of additional functional follow-up studies.
ER -