# Analysis of short tandem repeats linked to polyglutamine diseases from whole-genome sequencing reveals intermediate alleles of HTT associated with an early disease onset in C9orf72 carriers

## TL;DR

This study finds that intermediate alleles of the HTT gene are linked to earlier disease onset in patients with C9orf72 expansions, suggesting a genetic connection between polyglutamine diseases.

## Contribution

The study identifies HTT intermediate alleles as a novel genetic modifier of age at onset in C9orf72-related diseases using whole-genome sequencing.

## Key findings

- HTT intermediate alleles are associated with earlier disease onset in C9orf72 carriers (average difference of 9.42 years).
- No polyglutamine inclusions were found in a C9orf72 case with HTT-intermediate alleles.
- No somatic expansion of HTT was detected in blood samples of C9orf72/HTT carriers.

## Abstract

Carriers of the GGGGCC pathogenic expansion in C9orf72 can develop symptoms of frontotemporal dementia and/or amyotrophic lateral sclerosis, with variable and unpredictable ages at onset. Previous studies aiming to decipher the genetic bases of the clinical variability in this rare disease included bi-allelic polymorphisms, excluding short tandem repeats. Whole-genome sequencing data of 195 C9orf72 patients were used to consider all short tandem repeats linked to polyglutamine disorders as potential genetic modifiers given the existing links between C9orf72 and polyglutamine diseases. Intermediate alleles of HTT encoding huntingtin were associated with an earlier age at onset among C9orf72 carriers in the discovery cohort (n = 195, P = 0.0003) and in a European replication cohort (n = 145, P = 0.006). In the merged cohort (n = 340), the average difference of age at disease onset was 9.42 ± 2.14 years (P = 1.3 × 10e−5) between carriers and non-carriers of HTT-intermediate alleles. Neuropathology of one C9orf72 case heterozygous for HTT-intermediate allele showed typical TDP-43 inclusions related to the C9orf72 pathogenic expansion and was negative for polyglutamine inclusion. No somatic expansion of HTT was detected in blood of all C9orf72exp/HTT-intermediate carriers. If this study reinforces potential biological links between huntingtin and C9orf72 that remain to be explored, the results also illustrate the interest of considering short tandem repeats from whole-genome data in association studies which paves the way to more exhaustive approaches to explore the trait heritability due to short-tandem-repeats still hidden in the genome.

Whole-genome-sequencing of patients carrying pathogenic C9orf72 expansions was used to consider short-tandem-repeats linked to polyglutamine disorders as potential modifiers of frontotemporal-dementia/amyotrophic-lateral-sclerosis. Barbier et al. reported intermediate alleles of huntingtin associated with early disease onsets, highlighting links between C9orf72 and polyglutamine disorders, and emphasizing the role of short-tandem-repeats in disease variability.

Graphical Abstract