MRC Prion Unit at UCL, UCL Institute of Prion Diseases, London, UK.
South West Thames Regional Genetics Service, London, UK.
Nat Rev Neurol. 2021 Jan;17(1):23-36. doi: 10.1038/s41582-020-00416-1. Epub 2020 Nov 9.
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.
在痴呆症领域，临床遗传学检测技术已经取得了快速的发展，但在实际应用中仍有待进一步推广。阳性基因检测可提供精确的分子诊断，有助于受影响家族成员确定个人风险，为生殖选择提供依据，并为临床试验提供选择。确定痴呆症具体遗传病因的可能性取决于临床情况、发病年龄和家族史。由于痴呆症之间存在临床重叠、遗传异质性、多效性和并发突变，尝试将表型与单个基因相匹配是不可取的。目前，在大多数痴呆症病例中，适当的基因检测是下一代测序基因面板，尽管某些情况下需要特定类型的检测，如重复扩展检测。外显子组和全基因组测序在经济上变得可行，但却引发或加剧了一些复杂问题，如意义不明的变异、次要发现以及根据新信息重新分析的可能性。然而，数据分析和咨询的能力已经限制了基因检测的提供。需要向患者及其亲属提供可靠的信息，以使他们能够就检测、治疗和数据共享做出明智的选择；在提供这些信息时，必须考虑到痴呆症患者做出决策的能力。
