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  • Review Article
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Genetic testing in dementia — utility and clinical strategies

Abstract

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.

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 increase as treatment options become available because patients with a genetic diagnosis are good candidates for disease-modifying drug trials.

  • Additional tests are currently required to detect repeat expansions, but long-read sequencing will enable simultaneous testing for SNPs and repeat expansions once it becomes sufficiently reliable and accurate.

  • Genetic testing requires counselling on variants of uncertain significance, secondary findings and implications for relatives; in dementia disorders, mental capacity is an important consideration.

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Fig. 1: Diagnostic uncertainty and pleiotropy in dementia.
Fig. 2: Algorithm for genetic testing of patients with dementia.

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Acknowledgements

C.K. is supported by a Leonard Wolfson Foundation PhD fellowship. N.S.R. is supported by a University of London Chadburn Academic Clinical Lectureship. J.D.R. is supported by a Medical Research Council Clinician Scientist Fellowship (MR/M008525/1) and has received funding from the NIHR Rare Disease Translational Research Collaboration (BRC149/NS/MH). J.M.S. acknowledges the support of the National Institute for Health Research University College London Hospitals Biomedical Research Centre, Wolfson Foundation, ARUK (ARUK-PG2017-1946), Brain Research UK (UCC14191), Weston Brain Institute (UB170045), Medical Research Council, British Heart Foundation, and European Union’s Horizon 2020 research and innovation programme (Grant 666992). N.C.F. acknowledges support from the UK Dementia Research Institute, from the Rosetrees Trust and from the NIHR Biomedical Research Centre at University College Hospitals NHS Foundation Trust. S.J.T. has received grant funding for her Huntington disease research from the Medical Research Council (UK), the Wellcome Trust, the Rosetrees Trust, Takeda Pharmaceuticals, Cantervale Limited, the NIHR North Thames Local Clinical Research Network, the UK Dementia Research Institute, the Wolfson Foundation for Neurodegeneration and the CHDI Foundation. S.M. is supported by the Medical Research Council (UK) and the National Institute for Health Research Biomedical Research Centre at University College Hospitals NHS Foundation Trust.

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All authors contributed to the drafting and proofreading of the manuscript. C.K. produced the figures and S.M. had the original idea for this review article.

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Related links

Alzgene: http://www.alzgene.org/

Human Genetic Variation Database: http://www.hgvd.genome.med.kyoto-u.ac.jp/

Glossary

Allelic drop out

Failure to amplify one or both alleles during a sequencing reaction.

Breakpoints

Limits or borders of a structural variant where they link to the surrounding normal genomic sequence.

Paired-read sequencing

The process of sequencing a genomic fragment using adapters to both ends of the fragment, which improves reference sequence alignment and facilitates the analysis of repetitive regions.

Segregation analysis

Genetic analysis of affected and unaffected members of a family for their carrier status with regards to a particular genetic variant.

Anticipation

A phenomenon in which age at onset decreases and the severity of the phenotype increases from one generation to the next in some genetic diseases; typical of some trinucleotide repeat disorders in which the number of repeats is linked to the age at onset and the severity of disease.

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Koriath, C.A.M., Kenny, J., Ryan, N.S. et al. Genetic testing in dementia — utility and clinical strategies. Nat Rev Neurol 17, 23–36 (2021). https://doi.org/10.1038/s41582-020-00416-1

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