---
title: "Using Topologically Associated Domains to Prioritize Pathogenic Non-Coding Variants in Unresolved"
id: "biorxiv-0-identifying-putative-pathogenic-non-coding-variants-in-unresolved-rare-disease"
canonical_url: "https://medichelpline.com/clinical-feed/biorxiv-0-identifying-putative-pathogenic-non-coding-variants-in-unresolved-rare-disease"
content_type: "clinical_feed_article"
specialty: "General"
source_name: "bioRxiv (Biomedical Preprints)"
source_url: "https://www.biorxiv.org/content/10.64898/2026.09.17.752339v1?rss=1"
published_at: "2026-09-20T10:56:31.000Z"
evidence_level: "Verified Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# Using Topologically Associated Domains to Prioritize Pathogenic Non-Coding Variants in Unresolved
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/biorxiv-0-identifying-putative-pathogenic-non-coding-variants-in-unresolved-rare-disease
- **Specialty:** [General](https://medichelpline.com/clinical-feed/general.md)
- **Primary Source:** bioRxiv (Biomedical Preprints)
- **Source URL:** [Original Journal Publication](https://www.biorxiv.org/content/10.64898/2026.09.17.752339v1?rss=1)
- **Published At:** 2026-09-20T10:56:31.000Z
- **Evidence Rating:** Verified Feed
## Executive GIST (TL;DR)
- Unresolved rare disease affects roughly **300 million** people worldwide; about **50%** of these cases remain genetically unresolved after exome sequencing and/or whole genome sequencing, indicating a substantial diagnostic gap. - One contributor to missing diagnoses is rare variation in the **non-coding genome**: these variants are detected by whole genome sequencing but often not interpreted. - The authors developed the Genomic Analysis of Variants in Unresolved Rare Disease (**GAVURD**) system to systematically evaluate candidate pathogenic non-coding variants in unresolved rare disease probands. - **GAVURD** leverages **trio whole genome sequencing** alignment data as input, applies best practices for identifying de novo and rare inherited variants, and produces a short list of prioritized candidate non-coding variants for each proband. - The system links variants to human disease genes using **topologically associated domain (TAD)** data, thereby assigning non-coding variants to potential target genes based on 3D genome organization rather than linear distance alone. - Variants are rank-prioritized within GAVURD based on phenotypic overlap between the proband and candidate target genes, integrating genotype and phenotype information to focus follow-up. - As a proof-of-concept, GAVURD was applied to ten probands with unresolved rare disease and implicated six potentially causal non-coding variants where multiple lines of evidence supported pathogenicity. - The authors frame GAVURD as a tool to generate a high-value, prioritized set of candidate non-coding causal variants that can guide subsequent functional follow-up studies. - The study is presented as a preprint and has not been peer reviewed; funding declared includes an NIH training grant. No competing interests were declared. - Supplementary material and a downloadable PDF are available with the preprint; the work has been placed in the public domain by the authors.
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Gacita, Matthew Pahl, Manuel Diz Torres, Shiva Ganesan, Justin J. Blair, Khushbu Patel, Rajagopalan Ramakrishnan, Laura Conlin, Ingo Helbig, [ View ORCID Profile](http://orcid.org/0000-0003-2025-5302)Struan F.A. Grant doi: https://doi.org/10.64898/2026.09.17.752339 This article is a preprint and has not been certified by peer review [[what does this mean?](https://www.biorxiv.org/about/FAQ#unrefereed)]. Anthony M. Gacita 1 Division of Genetics and Genomics, Children's Hospital of Philadelphia; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Anthony%2BM.%2BGacita%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Gacita%20AM&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AAnthony%2BM.%2BGacita%2B) * [ORCID record for Anthony M. Gacita](http://orcid.org/0000-0002-5409-6103 "Open in new tab") Matthew Pahl 1 Division of Genetics and Genomics, Children's Hospital of Philadelphia; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Matthew%2BPahl%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Pahl%20M&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AMatthew%2BPahl%2B) Manuel Diz Torres 2 Division of Neurology, Children's Hospital of Philadelphia; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Manuel%2BDiz%2BTorres%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Torres%20MD&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AManuel%2BDiz%2BTorres%2B) Shiva Ganesan 2 Division of Neurology, Children's Hospital of Philadelphia; * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Shiva%2BGanesan%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Ganesan%20S&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AShiva%2BGanesan%2B) Justin J. 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Grant 4 Division of Genetics and Genomic Medicine, Children's Hospital of Philadelphia * [Find this author on Google Scholar](https://www.biorxiv.org/lookup/google-scholar?link_type=googlescholar&gs_type=author&author%5B0%5D=Struan%2BF.A.%2BGrant%2B "Open in new tab") * [Find this author on PubMed](https://www.biorxiv.org/lookup/external-ref?access_num=Grant%20SF&link_type=AUTHORSEARCH "Open in new tab") * [Search for this author on this site](https://www.biorxiv.org/search/author1%3AStruan%2BF.A.%2BGrant%2B) * [ORCID record for Struan F.A. Grant](http://orcid.org/0000-0003-2025-5302 "Open in new tab") * For correspondence: grants@chop.edu * [Abstract](https://www.biorxiv.org/content/10.64898/2026.09.17.752339v1)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_art/node:5795719/1) * [Info/History](https://www.biorxiv.org/content/10.64898/2026.09.17.752339v1.article-info)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_info/node:5795719/1) * [Metrics](https://www.biorxiv.org/content/10.64898/2026.09.17.752339v1.article-metrics)[](https://www.biorxiv.org/panels_ajax_tab/article_tab_metrics/node:5795719/1) * [Supplementary material](https://www.biorxiv.org/content/10.64898/2026.09.17.752339v1.supplementary-material)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_data/node:5795719/1) * [ Preview PDF](https://www.biorxiv.org/content/10.64898/2026.09.17.752339v1.full.pdf+html)[](https://www.biorxiv.org/panels_ajax_tab/biorxiv_tab_pdf/node:5795719/1) ![Loading](https://www.biorxiv.org/sites/all/modules/contrib/panels_ajax_tab/images/loading.gif) ## 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 Genomic Analysis of Variants in Unresolved Rare Disease (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. ### Competing Interest Statement The authors have declared no competing interest. ## Funder Information Declared National Institutes of Health, https://ror.org/01cwqze88, 5T32GM008638-30 Copyright [ The copyright holder has placed this preprint in the Public Domain.](https://creativecommons.org/publicdomain/zero/1.0/) It is no longer restricted by copyright. Anyone can legally share, reuse, remix, or adapt this material for any purpose without crediting the original authors. bioRxiv and medRxiv thank the following for their generous financial support: > The Chan Zuckerberg Initiative, Cold Spring Harbor Laboratory, the Sergey Brin Family Foundation, California Institute of Technology, Centre National de la Recherche Scientifique, Fred Hutchinson Cancer Center, Imperial College London, Massachusetts Institute of Technology, Stanford University, The University of Edinburgh, University of Washington, and Vrije Universiteit Amsterdam. [Donate to openRxiv ](https://www.zeffy.com/en-US/donation-form/donate-to-make-a-difference-10981) [ Back to top](https://www.biorxiv.org/content/10.64898/2026.09.17.752339v1?rss=1#page) [ Previous](https://www.biorxiv.org/content/10.64898/2026.09.17.751883v1 "Evolution of new cerebellar nuclei by excitatory progenitor diversification in the early rhombic lip")[Next ](https://www.biorxiv.org/content/10.64898/2026.09.18.752619v1 "The Genetic Architecture of Neonatal Deer Mouse Cries Implicates the Cerebellum in the Temporal Control of an Infant Social Behavior") Posted September 20, 2026. [ Download PDF](https://www.biorxiv.org/content/10.64898/2026.09.17.752339v1.full.pdf) Print/Save Options [Download PDF](https://www.biorxiv.org/content/biorxiv/early/2026/09/20/2026.09.17.752339.full.pdf)Full Text & In-line FiguresXML [More Info](https://www.biorxiv.org/about/FAQ#PrintOptions "More Information on Print/Save Options") [Supplementary Material ](https://www.biorxiv.org/content/10.64898/2026.09.17.752339v1.supplementary-material) [ Email](https://www.biorxiv.org/ "Email this Article") [ Share](https://www.biorxiv.org/) Identifying Putative Pathogenic Non-Coding Variants in Unresolved Rare Disease Patients Using Topologically Associated Domains Anthony M. Gacita, Matthew Pahl, Manuel Diz Torres, Shiva Ganesan, Justin J. Blair, Khushbu Patel, Rajagopalan Ramakrishnan, Laura Conlin, Ingo Helbig, Struan F.A. Grant bioRxiv 2026.09.17.752339; doi: https://doi.org/10.64898/2026.09.17.752339 This article is a preprint and has not been certified by peer review [[what does this mean?](https://www.biorxiv.org/about/FAQ#unrefereed)]. Share This Article: Copy [![Twitter logo](https://www.biorxiv.org/sites/all/modules/highwire/highwire/images/twitter.png)](https://www.biorxiv.org/highwire_log/share/twitter?link=http%3A%2F%2Ftwitter.com%2Fshare%3Furl%3Dhttps%253A%2F%2Fwww.biorxiv.org%2Fcontent%2F10.64898%2F2026.09.17.752339v1%26text%3DIdentifying%2520Putative%2520Pathogenic%2520Non-Coding%2520Variants%2520in%2520Unresolved%2520Rare%2520Disease%2520Patients%2520Using%2520Topologically%2520
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