medRxiv [Preprint]. 2024 May 21:2024.05.21.24307682. doi: 10.1101/2024.05.21.24307682.

ABSTRACT

Approximately 3% of the human genome consists of repetitive elements called tandem repeats (TRs), which include short tandem repeats (STRs) of 1-6bp motifs and variable number tandem repeats (VNTRs) of 7+bp motifs. TR variants contribute to several dozen mono- and polygenic diseases but remain understudied and “enigmatic,” particularly relative to single nucleotide variants. It remains comparatively challenging to interpret the clinical significance of TR variants. Although existing resources provide portions of necessary data for interpretation at disease-associated loci, it is currently difficult or impossible to efficiently invoke the additional details critical to proper interpretation, such as motif pathogenicity, disease penetrance, and age of onset distributions. It is also often unclear how to apply population information to analyses. We present STRchive (S-T-archive, http://strchive.org/ ), a dynamic resource consolidating information on TR disease loci in humans from research literature, up-to-date clinical resources, and large-scale genomic databases, with the goal of streamlining TR variant interpretation at disease-associated loci. We apply STRchive -including pathogenic thresholds, motif classification, and clinical phenotypes-to a gnomAD cohort of ∼18.5k individuals genotyped at 60 disease-associated loci. Through detailed literature curation, we demonstrate that the majority of TR diseases affect children despite being thought of as adult diseases. Additionally, we show that pathogenic genotypes can be found within gnomAD which do not necessarily overlap with known disease prevalence, and leverage STRchive to interpret locus-specific findings therein. We apply a diagnostic blueprint empowered by STRchive to relevant clinical vignettes, highlighting possible pitfalls in TR variant interpretation. As a living resource, STRchive is maintained by experts, takes community contributions, and will evolve as understanding of TR diseases progresses.

PMID:38826469 | PMC:PMC11142282 | DOI:10.1101/2024.05.21.24307682