STR calling and interpretation
Calling methodology
Emedgene uses ExpansionHunter by DRAGEN to call short tandem repeats (STR), also known as repeats expansions. Thirty clinical genes associated with diseases caused by repeat expansion are called in DRAGEN version 3.9 and presented in the platform. Those genes are: AFF2, AR, ATN1, ATXN1, ATXN10, ATXN2, ATXN3, ATXN7, ATXN8OS, C9ORF72, CACNA1A, CBL, CNBP, CSTB, DIP2B, DMPK, FMR1, FXN, GIPC1, GLS, HTT, JPH3, NIPA1, NOP56, PABPN1, PHOX2B, PPP2R2B, RFC1, TBP, TCF4.
Figure 1. Visual representation of STR calling with ExpansionHunter
(Left) Exact sizes of short repeats are identified from spanning reads that completely contain the repeat sequence.
(Middle) When the repeat length is close to the read length, the size of the repeat is approximated from the flanking reads that partially overlap the repeat and one of the repeat flanks.
(Right) If the repeat is longer than the read length, its size is estimated from reads completely contained inside the repeat (in-repeat reads). In-repeat reads anchored by their mate to the repeat region are used to estimate the size of the repeat up to the fragment length. When there is no evidence of long repeats with the same repeat motif elsewhere in the genome, pairs of in-repeat reads can also be used to estimate the size of long (greater-than-fragment-length) repeats.
Note*:* ExpansionHunter for STR calling is designed for use in PCR-free WGS only. While STR variants might be called in exome cases, the limitations are currently unknown and it is therefore not recommended for use.
Recommendation for interpretation
In light of our recent experience and an internal investigation by the Illumina’s scientific team, we believe it is appropriate to enable prioritization for a subset of STR loci, but not all loci typed by DRAGEN. This is due to technical genotyping challenges and/or lack of scientific evidence of pathogenicity for the remaining loci. Current list of genes where STR may be tagged when appropriate is provided below:
Gene | Associated Condition | Mode of Inheritance | Repeat Unit |
ATXN10 | Spinocerebellar ataxia 10 (SCA10) | Autosomal Dominant | ATTCT |
ATXN8OS | Spinocerebellar ataxia 8 (SCA8) | Autosomal Dominant | CTG |
ATN1 | Dentatorubral-pallidoluysian atrophy (DRPLA) | Autosomal Dominant | CAG |
ATXN1 | Spinocerebellar ataxia 1 (SCA1) | Autosomal Dominant | CAG |
ATXN2 | Spinocerebellar ataxia 2 (SCA2) | Semi-dominant | CAG |
ATXN3 | Spinocerebellar ataxia 3 (SCA3) | Autosomal Dominant | CAG |
ATXN7 | Spinocerebellar ataxia 7 (SCA7) | Autosomal Dominant | CAG |
CACNA1A | Spinocerebellar ataxia 6 (SCA6) | Autosomal Dominant | CAG |
DMPK | Myotonic dystrophy 1 (DM1) | Autosomal Dominant | CTG |
DMPK | Myotonic dystrophy 1, mild | Autosomal Dominant | CTG |
FMR1 | Fragile X tremor/ataxia syndrome (FXTAS) or Premature Ovarian Failure (POF) | X-linked | CGG |
FMR1 | Fragile X Syndrome (FXS) | X-linked | CGG |
HTT | Huntington's disease (HD) | Autosomal Dominant | CAG |
PPP2R2B | Spinocerebellar ataxia 12 (SCA12) | Autosomal Dominant | CAG |
TBP | Spinocerebellar ataxia 17 (SCA17) | Autosomal Dominant | CAG |
C9orf72 | Amyotrophic lateral sclerosis and/or frontotemporal dementia (FTDALS1) | Autosomal Dominant | GGGGCC |
AR | Spinal and bulbar muscular atrophy (SBMA) | X-linked | CAG |
FXN | Friedreich ataxia (FRDA) | Autosomal Recessive | GAA |
CNBP | Myotonic dystrophy 2 (DM2) | Autosomal Dominant | CCTG |
JPH3 | Huntington disease-like 2 (HDL2) | Autosomal Dominant | CTG |
NOP56 | Spinocerebellar ataxia 36 (SCA36) | Autosomal Dominant | GGCCTG |
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