Faculty Collaboration Database

A genome-wide approach for the discovery of novel repeat expansion disorders in the Undiagnosed Diseases Network cohort. Genet Med 2025 Aug;27(8):101462

Date

05/26/2025

Pubmed ID

40417743

Pubmed Central ID

PMC12318663

DOI

10.1016/j.gim.2025.101462

Scopus ID

2-s2.0-105009588600 (requires institutional sign-in at Scopus site)

Abstract

PURPOSE: The Undiagnosed Diseases Network is a National Institutes of Health funded research study that aims to solve a broad clinical spectrum of challenging rare disease cases. Participants receive care from multiple clinical specialists, who collaborate to perform deep phenotyping and state-of-the-art multiomics analyses. As bioinformatics of short-read sequencing has matured, the discovery of repeat expansion disorders (REDs) is accelerating. REDs comprise approximately 60 characterized disorders, which exhibit a broad spectrum of phenotypes. Thus, a largely unbiased genome-wide approach in a phenotypically diverse sample will add to the diagnostic depth, explore the limits of short-read genome analysis, and establish novel candidate RED loci.

METHODS: Here, we present a genome-wide analysis of repeat expansions conducted on 1018 genomes from the Undiagnosed Diseases Network. By leveraging 2 distinct bioinformatics tools, ExpansionHunter Denovo and STRling, we showed that repeat expansions can be accurately detected in short-read genomes.

RESULTS: We demonstrated that a genotype-first approach can diagnose atypical cases of known REDs and provide valuable clinical insights. We present clinical details on participants with expansions in ATXN7, DMPK, FMR1, GLS, HTT, RFC1, AFF3, and MARCH6. Importantly, we highlight 2 cases of juvenile Huntington disease that were discovered through our analysis. Finally, we present a list of novel candidate short tandem repeats (TR) that could potentially be pathogenic if expanded.

CONCLUSION: Importantly, our approach showcases the bioinformatic advancements in genome analysis for RED detection and highlights its practical applications.

Author List

Fazal S, Dashnow H, Dohrn MF, Raposo J, Hiatt L, Danzi MC, Xu IRL, Toro C, Adams DR, Usdin K, Hayward B, Kobren SN, Sunyaev SR, Spillmann RC, Shashi V, Rebelo A, Bademci G, Undiagnosed Diseases Network, Tekin M, Quinlan AR, Zuchner S

Authors

James Verbsky PhD, MD Professor in the Pediatrics department at Medical College of Wisconsin
Michael T. Zimmermann PhD Director, Associate Professor in the Data Science Institute department at Medical College of Wisconsin

MESH terms used to index this publication - Major topics in bold

Cohort Studies
Computational Biology
DNA Repeat Expansion
Genome, Human
Genome-Wide Association Study
Genotype
Humans
Male
Phenotype
Rare Diseases