Repeat expansions

ExpansionHunter

At certain places in the genome a short motif repeats many times. If the number of repeats passes a locus-specific threshold, neurological disease arises. Genome estimates the repeat number at defined loci in a targeted way.

REPEAT EXPANSIONS · THRESHOLDS normal range pathogenic HTT (CAG)n ≥ 40 Huntington's disease FMR1 (CGG)n 55-200 Fragile X syndrome C9orf72 (GGGGCC)n ≥ 30 ALS / FTD Thresholds are locus-specific; ExpansionHunter estimates the copy number from targeted reads.

Why repeats are special

An expansion can be unstable and grow across generations (anticipation). It often does not change a protein directly but disturbs transcription, splicing or creates toxic RNA. That is why the exact repeat count, not just its presence, is clinically decisive.

How Genome analyses

Genome uses ExpansionHunter. The tool aligns reads against a sequence-graph model of the locus and estimates the repeat count from it, even when individual reads do not fully span the repeat. Genome presents ExpansionHunter strictly as repeat evidence, not as small-variant evidence.

What Genome measures. The estimated repeat count per allele at targeted repeat loci, related to the locus-specific normal range and pathogenic threshold.

Related topics

Structural variantsLp(a) and KIV-2

Sources

  1. 1Dolzhenko et al., 2019 ExpansionHunter: a sequence-graph-based tool to analyze variation in short tandem repeat regions. Bioinformatics 35:4754–4756. doi.org/10.1093/bioinformatics/btz431
  2. 2Depienne & Mandel, 2021 30 years of repeat expansion disorders: what have we learned and what are the remaining challenges?. American Journal of Human Genetics 108:764–785. doi.org/10.1016/j.ajhg.2021.03.011