Skip to content

09-str-expansions.md

Latest commit

 

History

History
54 lines (42 loc) · 2.66 KB

09-str-expansions.md

File metadata and controls

54 lines (42 loc) · 2.66 KB

Step 9: Short Tandem Repeat (STR) Expansion Screening

What This Does

Screens for pathogenic repeat expansions — a class of mutations invisible to both DeepVariant and Manta. In these diseases, a short DNA sequence (3-6 bases) gets repeated too many times.

Why

STR expansions cause ~40 known neurological/neuromuscular diseases including Huntington's, Fragile X, Friedreich's ataxia, ALS/FTD, myotonic dystrophy, and multiple spinocerebellar ataxias.

Tool

  • ExpansionHunter v5.0.0 (Illumina) — upgraded from v2.5.5. Adds multithreading, improved long-repeat estimation, and a bundled GRCh38 variant catalog (31 pathogenic loci)

Docker Image

quay.io/biocontainers/expansionhunter:5.0.0--hc26b3af_5
  • Binary: ExpansionHunter (on PATH)
  • GRCh38 catalog: /usr/local/share/ExpansionHunter/variant_catalog/grch38/variant_catalog.json (31 pathogenic loci)

Key Disease Thresholds

Disease Gene Repeat Unit Normal Pathogenic
Huntington's HTT CAG <27 >35
Fragile X FMR1 CGG <45 ≥55 (premutation) / >200 (full)
Friedreich's Ataxia FXN GAA <33 >66
ALS/FTD C9ORF72 GGCCCC <24 >30
Myotonic Dystrophy 1 DMPK CTG <35 >50
SCA1 ATXN1 CAG <33 >39
SCA2 ATXN2 CAG <22 >33

FMR1 Clinical Zones

FMR1 (Fragile X) has four distinct clinical zones — the intermediate zone (45-54 repeats) is often omitted but clinically relevant:

Zone Repeats Clinical Significance
Normal <45 No risk
Intermediate (gray zone) 45-54 Not affected, but repeats may expand in offspring. Genetic counseling recommended for carriers.
Premutation 55-200 Risk of FXTAS (tremor/ataxia, males >50), FXPOI (premature ovarian insufficiency). Offspring at risk of full expansion.
Full mutation >200 Fragile X syndrome (intellectual disability, behavioral features). Penetrance varies by sex and methylation.

Command

./scripts/09-expansion-hunter.sh your_name male
# or: ./scripts/09-expansion-hunter.sh your_name female

The second argument (male/female) is required — it affects X-linked loci (FMR1, AR): males have one allele, females have two.

Notes

  • Uses ExpansionHunter v5.0.0 (quay.io/biocontainers/expansionhunter:5.0.0--hc26b3af_5)
  • v5 CLI: --reads, --reference, --variant-catalog (JSON file), --output-prefix (auto-generates .vcf, .json)
  • The 31-locus GRCh38 variant catalog is bundled inside the container at /usr/local/share/ExpansionHunter/variant_catalog/grch38/variant_catalog.json
  • Short-read WGS can reliably detect expansions up to ~150 repeats; very large expansions (>1000) are less accurate