# Attenuated huntingtin gene CAG nucleotide repeat size in individuals with Lynch syndrome

## TL;DR

This study found that individuals with Lynch syndrome have smaller CAG repeats in the huntingtin gene, suggesting DNA repair genes may influence repeat expansion diseases.

## Contribution

The study provides novel evidence that MMR gene haploinsufficiency may restrain HTT CAG repeat size.

## Key findings

- The MLH1 subgroup had significantly lower CAG repeat sizes compared to controls.
- All LS subgroups showed lower frequencies of unstable HTT intermediate alleles.
- LS subgroups had lower HTT somatic CAG repeat expansion index values compared to controls.

## Abstract

DNA mismatch repair (MMR) is thought to contribute to the onset and progression of Huntington disease (HD) by promoting somatic expansion of the pathogenic CAG nucleotide repeat in the huntingtin gene (HTT). Here we have studied constitutional HTT CAG repeat size in two cohorts of individuals with Lynch syndrome (LS) carrying heterozygous loss-of-function variants in the MMR genes MLH1 (n = 12/60; Lund cohort/Bochum cohort, respectively), MSH2 (n = 15/88), MSH6 (n = 21/23), and controls (n = 19/559). The sum of CAG repeats for both HTT alleles in each individual was calculated due to unknown segregation with the LS allele. In the larger Bochum cohort, the sum of CAG repeats was lower in the MLH1 subgroup compared to controls (MLH1 35.40 CAG repeats ± 3.6 vs. controls 36.89 CAG repeats ± 4.5; p = 0.014). All LS genetic subgroups in the Bochum cohort displayed lower frequencies of unstable HTT intermediate alleles and lower HTT somatic CAG repeat expansion index values compared to controls. Collectively, our results indicate that MMR gene haploinsufficiency could have a restraining impact on constitutional HTT CAG repeat size and support the notion that the MMR pathway is a driver of nucleotide repeat expansion diseases.