Massively parallel identification of functionally consequential noncoding genetic variants in undiagnosed rare disease patients.

Creator(s)

Jasmine A. McQuerry, Children's Mercy HospitalFollow
Merry Mclaird, Children's Mercy HospitalFollow
Samantha N. Hartin, Children's Mercy Hospital
John C. Means, Children's Mercy HospitalFollow
Jeffrey J. Johnston, Children's Mercy HospitalFollow
T Pastinen, Children's Mercy HospitalFollow
Scott T. Younger, Children's Mercy HospitalFollow

Document Type

Article

Publication Date

5-9-2022

Identifier

DOI: 10.1038/s41598-022-11589-8

Abstract

Clinical whole genome sequencing has enabled the discovery of potentially pathogenic noncoding variants in the genomes of rare disease patients with a prior history of negative genetic testing. However, interpreting the functional consequences of noncoding variants and distinguishing those that contribute to disease etiology remains a challenge. Here we address this challenge by experimentally profiling the functional consequences of rare noncoding variants detected in a cohort of undiagnosed rare disease patients at scale using a massively parallel reporter assay. We demonstrate that this approach successfully identifies rare noncoding variants that alter the regulatory capacity of genomic sequences. In addition, we describe an integrative analysis that utilizes genomic features alongside patient clinical data to further prioritize candidate variants with an increased likelihood of pathogenicity. This work represents an important step towards establishing a framework for the functional interpretation of clinically detected noncoding variants.

Journal Title

Sci Rep

Volume

12

Issue

1

First Page

7576

Last Page

7576

MeSH Keywords

Genome; Genomics; Humans; Rare Diseases; Undiagnosed Diseases; Whole Genome Sequencing

Keywords

Genome; Genomics; Humans; Rare Diseases; Undiagnosed Diseases; Whole Genome Sequencing

Comments

This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/.

Publisher's Link: https://www.nature.com/articles/s41598-022-11589-8

Recommended Citation

McQuerry JA, Mclaird M, Hartin SN, et al. Massively parallel identification of functionally consequential noncoding genetic variants in undiagnosed rare disease patients. Sci Rep. 2022;12(1):7576. Published 2022 May 9. doi:10.1038/s41598-022-11589-8