# Investigating the contribution of non-coding genetic variation to rare disorders

> **NIH NIH DP5** · UNIVERSITY OF WASHINGTON · 2024 · $388,750

## Abstract

PROJECT SUMMARY/ABSTRACT
Genetic testing is rapidly emerging as a cornerstone of medicine, enabling targeted therapies for patients with
both common and rare disorders, and empowering patients, families and communities with knowledge about
their condition. However, despite significant advances over the past decade, including the introduction of
clinical whole genome sequencing, clinical genetics remains largely limited to the study of less than 1% of the
genome, the exome. This limitation is thought to underlie the fact that clinical genomic sequencing is
unsuccessful in elucidating the culprit pathogenic variant(s) for the majority of patients with presumed
monogenic disorders who undergo testing. It is hypothesized that a significant percentage of these patients
harbor pathogenic non-coding variants that disrupt the gene regulatory architecture of known Mendelian
genes, a class of variants poorly illuminated using current sequencing approaches. Directly addressing this
limitation requires a wholesale revision of how genetic testing is performed and interpreted, as is outlined in
this proposal. Specifically, this proposal aims to overcome this fundamental limitation of human genetics by
leveraging a novel approach we recently developed for simultaneously mapping the genetic and epigenetic
landscape of a sample, thereby illuminating the functional impact of non-coding genetic variants that disrupt
local chromatin architecture and gene regulatory patterns – Whole Epi-Genome Sequencing (WEGS). Using
this approach, we plan to directly test the hypothesis that rare non-coding genetic alterations contribute to
monogenic disorders. In Aim 1, we will use the WEGS approach to characterize the gene regulatory impact of
non-coding sequence, structural and epigenetic alterations in healthy individuals as well as patients with known
imprinting disorders. The goal of this aim is to establish the sensitivity and power of WEGS for identifying
genetic variants that disrupt local chromatin architecture and gene regulatory patterns and improve our
understanding of the functional impact of non-coding genetic variation. In Aim 2, we will directly evaluate the
contribution of rare non-coding genetic alterations to monogenic disorders by applying WEGS to patients with
suspected monogenic disorders for whom whole exome or genome sequencing has previously been non-
diagnostic. Overall, this proposal has the potential to dramatically change how we approach genomic testing
and our understanding of the impact of non-coding sequence and structural variation on gene regulatory
patterns and human disease.

## Key facts

- **NIH application ID:** 10914101
- **Project number:** 5DP5OD029630-05
- **Recipient organization:** UNIVERSITY OF WASHINGTON
- **Principal Investigator:** Andrew Ben Stergachis
- **Activity code:** DP5 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2024
- **Award amount:** $388,750
- **Award type:** 5
- **Project period:** 2020-09-15 → 2026-08-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10914101

## Citation

> US National Institutes of Health, RePORTER application 10914101, Investigating the contribution of non-coding genetic variation to rare disorders (5DP5OD029630-05). Retrieved via AI Analytics 2026-05-21 from https://api.ai-analytics.org/grant/nih/10914101. Licensed CC0.

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