OVERVIEW

TR SPECIFIC DETAILS

RESOURCES

Evaluating allele(s)

Allele Size

Premutations

Contraction/expansion

Somatic mosaicism

Compare allele of interest to available thresholds for benign, intermediate, and pathogenic size.

Evaluate whether an allele may be classified within the intermediate range as a premutation-- this may have implications for patient presentation (mild or atypical phenotype) or for family members.

While most TR diseases are caused by expansions, contractions are speculated to lead to disease in specific loci where the reference allele is highly constrained. Consider whether an allele may be a pathogenic contraction versus an expansion.

Allelic instability may be tissue-specific; evaluate the sampled tissue and whether an allele may be a pathogenic size in the relevant tissue if the allele approaches a pathogenic threshold.

STRchive

Sequence Composition

Motif classification

Interruptions

Compare genotyped sequence motifs with reference and known TR sequences.

Determine if genotyped motif is benign, pathogenic, or of unknown consequence.

Assess motif sequence purity, as interruptions may increase or decrease penetrance, disease severity, or age of onset.

STRchive, Rajan-Babu et al., 2024.

Genotype quality

Read visualization

Technology

Check genotype quality and read support to filter unreliable calls.

Review read visualizations for alleles of similar size to assess expected read support and pattern of interruptions.

Appraise the molecular and sequencing technologies used to identify the allele and how this may impact reliability of calls.

gnomAD, Tanudisastro et al., 2024, Chaisson et al., 2023

Allele frequency

Ancestry-specific

Polymorphic distribution

Determine allele frequency within broader population; rare mutations are more likely to underlie rare disease.

Populations with different ancestries may have different allelic distributions and thresholds for pathogenicity; review the allele in the context of the relevant population if possible.

Given the highly polymorphic aspect of TRs, there are far more alleles likely to be present in a population at most loci than variants such as SNVs. As this may deflate exact allelic frequency, consider whether the allele falls outside of the normal distribution of alleles in addition to its exact frequency.

gnomAD, WebSTR, STRipy, TRGT database, TR-Atlas

Inheritance pattern

Mixed mutation types

Assess both alleles (if present) in case of recessive condition.

Consider non-TR, potentially compounding variants in second allele.

STRchive, ClinVar, ClinGen

Evaluating phenotype

Genotype-phenotype correlation

Anticipation

Reduced penetrance

Atypical presentation

Compare clinical history to symptoms

associated with gene (if any).

TR diseases may demonstrate anticipation, where disease severity increases and age of onset decreases by generation as alleles expand through transmission. Consider family history.

Penetrance can vary due to genetic modifiers and allelic attributes (motif, interruptions, etc.). Recall that a pathogenic genotype may not indicate current or future disease.

TR disease can present with immensely variable phenotypes, both in terms of severity and specific symptoms. Often, there is an inverse correlation between allele size and age of onset, which can lead to early and late-onset diseases outside of the conventional range.

OMIM, GeneReviews, Orphanet

Assess whether patient history matches reported disease age of onset range.

STRchive

Evaluating the locus

Known disease association

Predicted pathogenicity

Evaluate whether the locus has established association with TR disease by comparing to current catalogs.

There are loci that, while not associated with documented disease, have been predicted to be pathogenic through machine learning-based predictions. Additionally, manual comparison to known disease loci can inform the prediction of pathogenicity at novel loci based on known mechanisms of disease (e.g., polyalanine/glutamine tracts.)

STRchive, RExPRT

Identify whether the gene has previous gene-disease associations documented for non-TR variant types.

ClinGen, OMIM, GenCC

Genomic region

Proximity to another TR locus

The genomic region in which a locus is present is highly informative: whether coding/non-coding, whether it overlaps genetic elements such as promoters/enhancers, and whether nearby variants have known disease relevance.

Several TR disease loci are found within the same gene. TR locus proximity may indicate potential pathogenicity, but also may lead to inflated allele estimation. Leverage nearby loci to inform variant interpretation.

STRchive, ClinVar, UCSC Genome Browser

The complexity and heterogeneity of TR loci means clinical and biological information may not be available in all cases. We recommend reviewing pertinent literature (cataloged by STRchive) and using best judgment when prioritizing variants.