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.
STR expansions cause ~40 known neurological/neuromuscular diseases including Huntington’s, Fragile X, Friedreich’s ataxia, ALS/FTD, myotonic dystrophy, and multiple spinocerebellar ataxias.
--variant-catalog flag, but the Docker image used here ships v2.5.5weisburd/expansionhunter:latest
/ExpansionHunter/bin/ExpansionHunter/pathogenic_repeats/GRCh38/ (38 disease loci)| 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 (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. |
--repeat-specs (directory), not --variant-catalog--log is REQUIRED (missing it causes silent exit)--sex affects X-linked loci (FMR1, AR): males have one allele, females have two