STR tiering

When estimating repeat sizes, ExpansionHunter provides confidence intervals and an average for each allele (i.e., x-y and avg(x,y)). For increased sensitivity, the maximum value (i.e., y) of these estimations is taken for each allele and locus to assign tier.

Note

The average value is displayed in the Interpretation Portal, as that value is expected to be closer to the real allele size.

STR loci that are green in PanelApp for the panel(s) applied for analysis will be tiered. Two different ranges of thresholds are used when tiering:

Tier 1

The repeat-length for the locus is greater than or equal to the pathogenic threshold.

Tier 2

The repeat-length is greater than or equal to the threshold for normal alleles but less than the pathogenic threshold.

Tier Null

The repeat-length is less that the threshold for normal alleles.

Additional information

STRs are only tiered for affected members of a family.

For biallelic loci (i.e., FXN), affected individuals homozygous for a pathogenic expansion or compound heterozygous (STR and SNV) are also tiered. This is achieved using the same approach as is used for tiering SNVs and Indels using the incomplete penetrance pipeline for an autosomal recessive mode of inheritance. Due to a limitation of the ExpansionHunter algorithm, in some cases, biallelic expansions of the FXN expansion may be incorrectly detected as monoallelic expansions.

Note

Internal population repeat size frequencies are not currently being used for STR filtering or tiering.

Special notes regarding FMR1

Full FMR1 expansions (>200 repeats) cannot be distinguished from pre-pathogenic expansions and therefore in majority of cases will be reported as preexpasions in Tier 2.

Tiering of FMR1 was introduced in Grace release. For the cases processed with the earlier version of tiering, that was not considering FMR1 despite it being green in PanelApp, a warning will be displayed in the Interpretation Portal notifying that FMR1 was not considered in tiering.