Genotype–phenotype considerations in neurogenetic disease

Mutation within a patient’s DNA results in the clinical manifestation of neurogenetic disease. This relationship between genotype and phenotype lies at the heart of genetic diagnosis and forms the basis of the strategies upon which diagnostic testing is pursued. However, genotype–phenotype correlations can be complex across neurological disease and examples abound where genotype and phenotype may become dissociated from one another through variations in penetrance and expressivity, complicating the clinical evaluation and impeding diagnosis, particularly for clinically heterogeneous conditions. Improvements in technology, such as next-generation sequencing, have led to advancements in variant analysis, expansion of the scope of clinical disease, and the development of resources to bring this information to the clinic. Here we provide an overview of the challenges in correlating genotype to phenotype and vice versa, discuss how these challenges arise in clinical practice, and present strategies on how they can be effectively overcome.