Genetic testing in dementia — utility and clinical strategies

Techniques for clinical genetic testing in dementia disorders have advanced rapidly but remain to be more widely implemented in practice. A positive genetic test offers a precise molecular diagnosis, can help members of an affected family to determine personal risk, provides a basis for reproductive choices and can offer options for clinical trials. The likelihood of identifying a specific genetic cause of dementia depends on the clinical condition, the age at onset and family history. Attempts to match phenotypes to single genes are mostly inadvisable owing to clinical overlap between the dementias, genetic heterogeneity, pleiotropy and concurrent mutations. Currently, the appropriate genetic test in most cases of dementia is a next-generation sequencing gene panel, though some conditions necessitate specific types of test such as repeat expansion testing. Whole-exome and whole-genome sequencing are becoming financially feasible but raise or exacerbate complex issues such as variants of uncertain significance, secondary findings and the potential for re-analysis in light of new information. However, the capacity for data analysis and counselling is already restricting the provision of genetic testing. Patients and their relatives need to be given reliable information to enable them to make informed choices about tests, treatments and data sharing; the ability of patients with dementia to make decisions must be considered when providing this information. In this Review, the authors discuss how technological advances are enabling clinical genetic testing for various dementia disorders. Additionally, they consider which types of test are appropriate for which patients and address the ethical issues that can be raised by genetic testing in these disorders. Key points For typical dementia, the most appropriate genetic test is usually a gene panel and C9orf72 expansion testing, which balances the likelihood of discovery with costs and minimizes variants of uncertain significance. Single-gene tests are warranted in specific situations, including typical Huntington disease, prion disease or to confirm a known familial mutation; atypical syndromes can necessitate whole-exome sequencing (WES) or whole-genome sequencing (WGS) and C9orf72 expansion testing. Discovery rates with WES and WGS are similar to those with gene panels, but WES and WGS data can be re-analysed when new information becomes available. The uptake of predictive testing is currently low but could i