2022 Entry Clinical Fellowship
Intergenerational Huntington Disease Study
Huntington’s disease (HD) is a genetic disease leading to a movement disorder, dementia and psychiatric symptoms. This project is a sperm study aiming to understand more about inheritance of the huntingtin gene to improve genetic counselling in HD.
DNA is made up of four molecules; A(adenine), T(thymine), C(cytosine) and G(guanine). It contains many areas called ‘repeat regions’ where there are repetitive combinations of these four molecules. The Huntington gene, huntingtin, is an example of a repeat region where there are repeated units of C, A and G where 1 CAG unit is equal to 1 repeat. Normally in the population there are up to 26 CAG repeat units but in those carrying the Huntington’s disease gene, there are 36 or more repeats.
There are over 50 human diseases caused by the presence too many repeats in different regions throughout our DNA. HD is one of them. This group of diseases is called the repeat expansion disorders (REDs).
We know in HD (and many REDs) that when the disease is inherited from parent to child, the length of the gene can sometimes expand or contract in sperm. This can mean sometimes children inherit a different sized gene compared to their parent. Expansions can lead to the child developing symptoms of HD earlier than their parent, termed ‘genetic anticipation’. Although genetic anticipation is widely recognised, the reason it happens in some families and not others is not understood.
This project involves donation of blood and sperm from men with HD for genetic analysis to characterise patterns of huntingtin CAG change in sperm and hopes to identify genetic factors that may be causative. This will improve understanding of the inheritance risk of the huntingtin gene and its risk of causing childhood (juvenile) disease. Additionally this may identify new biological pathways for further investigation.
Genetic modifiers of repeat expansion disorders
Emerging Topics in Life Sciences 2023 Oct 20:ETLS20230015.doi: 10.1042/ETLS20230015