Delineating the role of HTT Cis-Variants in the pathogenesis of Huntington disease

Huntington disease (HD) is a fatal neurodegenerative disorder without disease modifying therapies.

It is well known that HD is caused by an expanded CAG repeat in the huntingtin (HTT) gene leading to translation of a mutant HTT (mHTT) protein with an expanded polyglutamine stretch in the whole body. However, all clinical trials aiming to reduce levels of mHTT have so far failed. There is an inverse correlation between the length of the CAG repeat and the age of onset of HD.

Several large genetic studies including genome-wide and transcription-wide association studies have revealed important genetic modifiers of age-of-onset with cis-variants in HTT suggested to exert major effects.

However, these variants have not been considered in the characterization of clinical cohorts of individuals with HD including in the development of or inclusion for clinical trials aiming to modify disease progression. Also, the impact of the genetic variants on the function of mHTT or on neuropathology is not known.

Here we propose to fill an important and urgent gap in the knowledge of clinical genetics in HD.

We will delineate the role of cis-variants in HTT identified in large -omics studies in the pathogenesis of HD (delCAA-HD) using a combination of clinical cohorts and novel animal and cellular models of HD.

The delCAA consortium is composed of five international leading research laboratories, each with recognized and complementary expertise in various aspects of HD.