C9orf72 associated motor neurone disease (MND):investigating the genetic penetrance, expressivity, metabolic and inflammatory clinic-ready biomarkers

The hexanucleotide intronic expansion in C9orf72 is the most common Mendelian cause of MND, but we still have limited understanding of the disease penetrance, expressivity of severe compared with mild disease, the exact length and presence of interruptions in the C9orf72 repeat expansion in patients as compared with phenotype and associated wet biomarkers, which may help us with prognostication in the clinical setting.

With this proposal, we aim to use parallel and complementary approaches to address these questions. First, we will use the transformative UK BioBank, the largest prospective data of middle age to old people, to understand the penetrance of C9orf72. Secondly, we will concentrate on C9orf72 expansions from MND patients from UCL, QMUL and Cambridge to perform in depth DNA and RNA long-read PacBio Reviosequencing to identify alterations of the C9orf72 architecture that may link to differential clinical manifestations.

We will complement this work with state-of-the-art biomarker investigation using the NUcleic acid Linked Immuno-Sandwich Assay (NULISA) CNS panel of 120 biomarkers combined with additional custom poly(GP) dipeptide repeat proteins (DPRs) and circulating miR-181 levels. With this work we aim to accurately define age-related C9orf72 penetrance, identify modifiers of C9orf72 disease manifestation that could prove to benovel therapeutic targets as well as biomarkers of MND and disease progression.

This work will also improve our understanding of C9orf72 prognosis and improve patient genetic counselling and patient stratification in clinical trials.