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VUStruct: a compute pipeline for high throughput and personalized structural biology.

Christopher W Moth¹, Jonathan H Sheehan², Abdullah Al Mamun¹

¹Departments of Chemistry, Pharmacology, and Biomedical Informatics; Center for Structural Biology and Institute of Chemical Biology; Vanderbilt Univ., Nashville, TN 37232, USA.

Biorxiv : the Preprint Server for Biology

|August 16, 2024

Summary

VUStruct analyzes genetic variants of unknown significance (VUS) using 3D protein structures, aiding rare disease diagnosis. This computational tool enhances clinical interpretation and research by predicting molecular impacts and identifying digenic disease risks.

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Area of Science:

Genomic Medicine
Computational Biology
Structural Bioinformatics

Background:

Interpreting genetic variants of unknown significance (VUS) is crucial for diagnosing rare genetic disorders.
Current diagnostic methods rely on gene-phenotype databases and DNA scoring, which may lack detailed molecular insights.
The increasing availability of protein 3D structures, genomic data, and AI necessitates advanced analytical tools.

Purpose of the Study:

To introduce VUStruct, a web-accessible, High-Performance Computing (HPC) pipeline for analyzing the molecular impact of VUS within 3D protein structures.
To supplement existing diagnostic approaches by providing deeper insights into variant pathogenicity.
To support both clinical rare disease diagnosis and fundamental research in genomics and biochemistry.

Main Methods:

VUStruct maps missense variants onto selected protein structures.
It performs energy-based stability assessments, pathogenicity predictions via spatial clustering, and machine learning analyses for binding surface and post-translational modification site disruptions.
The pipeline also identifies potential digenic disease associations within sets of VUS.

Main Results:

VUStruct has been applied to over 175 Undiagnosed Disease Network (UDN) patient cases, informing clinical decisions and additional testing.
The tool has successfully guided research directions for academic collaborators in computational genomics and wet lab studies.
Specific case examples demonstrate VUStruct's critical role in resolving patient diagnoses.

Conclusions:

VUStruct is a mature, extensible software pipeline that effectively integrates 3D protein structure analysis for VUS interpretation.
It provides valuable molecular context, aiding clinicians and researchers in rare disease diagnosis and genetic research.
The pipeline's utility is demonstrated by its impact on clinical case resolution and research advancement.