criTRia: A Classification System and Evidence Criteria for Tandem Repeat Locus-Disease Relationships

Area of Science:

• Genetics
• Genomic Medicine
• Bioinformatics

Background:

• Tandem repeats (TRs), encompassing short tandem repeats (STRs) and variable number tandem repeats (VNTRs), are associated with over 50 Mendelian diseases.
• Existing frameworks for gene-disease relationship evaluation inadequately address the complexities of TRs, leading to misclassification and underdiagnosis of TR disorders.

Purpose of the Study:

• To develop and validate criTRia, a novel scoring framework for accurately evaluating TR locus-disease relationships at the locus level.
• To improve the classification consistency and clinical integration of TRs in genetic medicine.

Main Methods:

• Developed criTRia, a scoring framework building on ClinGen best practices with TR-specific evidence categories and reweighted scoring.
• Applied criTRia to curate 65 TR loci from the STRchive database.
• Compared criTRia curations with existing gene-level curations from nine Gene Curation Coalition (GenCC) groups.

Main Results:

• criTRia enabled the evaluation of 65 TR loci, including 7 previously unevaluated by GenCC.
• Significant disagreements were observed in 17 loci between criTRia and GenCC evaluations, impacting diagnostic panel recommendations.
• The framework facilitated the curation of 77 TR locus-disease associations and identified four contradictory associations.

Conclusions:

• The criTRia framework offers a reproducible methodology for assessing TR locus-disease associations by incorporating TR-specific evidence.
• Improved classification consistency and a foundation for integrating TRs into clinical genetic medicine are established.
• The study enhances the potential for more accurate diagnoses of tandem repeat disorders.