Dravet syndrome (DS) is a rare, but potentially devastating, genetic disease. For the many people who have the condition, its effects can be severe, including seizures that can be difficult to treat, risk of premature death, and other features that are wide-ranging and variable including intellectual disability, autism, and walking difficulties. Interestingly, although it is known that DS is caused by detrimental mutations in the gene sodium voltage-gated channel alpha subunit 1 (SCN1A), an identical SCN1A mutation inherited by multiple members of a family can cause DS in one person, whilst others may be unaffected or have only mild disease. There is currently no explanation as to why the clinical presentation of the disease is so wide ranging even in individuals with the exact same mutation in SCN1A.
We hypothesize that at least some of the differences that are seen between people with DS is due to variation in the genome beyond the “casual” SCN1A mutation. This idea has been explored in neurodevelopmental conditions at a broad level, and in other rare genetic conditions, such as the fatal genetic neurodegenerative condition, Huntington’s disease. Genetic studies in this rare disease, looking beyond the single known genetic “cause”, have identified important additional genetic factors that modify, for example, the age of onset of the disease, and have provided fundamental insights with important management implications.
In this multi-year research project (~36 months), we aim to uncover additional genetic factors that may contribute to the spectrum of health issues associated with DS by comparing the genomes of a cohort of 1000 well characterised individuals (e.g. detailed medical history, treatment-response information) with DS to a cohort of healthy individuals from the UK biobank. To achieve this, we will make use of cutting-edge genetic analysis tools. Understanding, how variation beyond the detrimental SNC1A mutation impacts on the clinical presentation of DS will have implications for the management and treatment of individuals with DS and potentially have wide-ranging social and economic benefits.