Somatic Mosaicism of the HTT Cag Repeat in Intermediate Allele Carriers with Neurocognitive Symptoms Compatible with Huntington Disease

Ruiz de Sabando, A., Ciosi, M. , Galbete, A., Monckton, D. G. and Ramos-Arroyo, M. A. (2022) Somatic Mosaicism of the HTT Cag Repeat in Intermediate Allele Carriers with Neurocognitive Symptoms Compatible with Huntington Disease. EHDN2022 Plenary Meeting - A: Pathogenic mechanisms, Bologna, Italy, 16-18 September 2022. (doi: 10.1136/jnnp-2022-ehdn.1)

Abstract

We aimed to determine the possible role of CAG somatic expansions on the clinical expression of intermediate allele (IA) carriers of the HTT gene, responsible for Huntington disease (HD). We performed exon one sequencing analysis of the HTT gene on peripheral blood DNA in a Spanish cohort of asymptomatic IA carriers (n=55), symptomatic IA carriers (n=86) and HD subjects (n=124). Additionally, we investigated different brain regions of an individual carrying an HTT allele with 33 CAGs, with neurocognitive symptoms. Linear regression models were used to analyse the association between CAG length and age with somatic mosaicism. Symptomatic IA carriers presented with motor (80%), cognitive (20%) and/or behavioural (22%) signs, and an average age of onset of 58.7 years±18.6. Somatic mosaicism is CAG- and age-dependent in alleles of CAG≥27 CAGs, with b=0.04 (95% CI: 0.035-0.046), and b=0.001 (95% CI: 0.001-0.002), respectively, for all IAs. There was no statistical difference between HTT somatic mosaicism in symptomatic vs asymptomatic IA carriers (p=0.066). Somatic expansions of +1 and +2 CAGs were detected in the brain of the individual with 33 CAGs, with the highest expansion ratio observed in the putamen, where up to 10% of the DNA molecules underwent somatic expansion. In conclusion, somatic CAG expansions observed in blood cannot explain, overall, the neurocognitive signs of IA carriers. However, somatic instability occurs in IAs, which changes with CAG number and age; therefore, the presence of cells in the brain that express up to +2 CAGs may be important when considering the phenotypes of those alleles close to the pathological threshold.

• Item Type: Conference or Workshop Item
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Monckton, Professor Darren and Ciosi, Dr Marc
• Authors: Ruiz de Sabando, A., Ciosi, M., Galbete, A., Monckton, D. G., and Ramos-Arroyo, M. A.
• College/School: College of Medical Veterinary and Life Sciences > School of Molecular Biosciences