Zampatti Stefania, Ragazzo Michele, Peconi Cristina, Luciano Serena, Gambardella Stefano, Caputo Valerio, Strafella Claudia, Cascella Raffaella, Caltagirone Carlo, Giardina Emiliano
Genomic Medicine Laboratory UILDM, IRCCS Fondazione Santa Lucia, 00179 Rome, Italy.
Department of Biomedicine and Prevention, Tor Vergata University of Rome, 00133 Rome, Italy.
J Pers Med. 2021 May 26;11(6):474. doi: 10.3390/jpm11060474.
Dementing disorders are a complex group of neurodegenerative diseases characterised by different, but often overlapping, pathological pathways. Genetics have been largely associated with the development or the risk to develop dementing diseases. Recent advances in molecular technologies permit analyzing of several genes in a small time, but the interpretation analysis is complicated by several factors: the clinical complexity of neurodegenerative disorders, the frequency of co-morbidities, and the high phenotypic heterogeneity of genetic diseases. Genetic counselling supports the diagnostic path, providing an accurate familial and phenotypic characterisation of patients. In this review, we summarise neurodegenerative dementing disorders and their genetic determinants. Genetic variants and associated phenotypes will be divided into high and low impact, in order to reflect the pathologic continuum between multifactorial and mendelian genetic factors. Moreover, we report a molecular characterisation of genes associated with neurodegenerative disorders with cognitive impairment. In particular, the high frequency of rare coding genetic variants in dementing genes strongly supports the role of geneticists in both, clinical phenotype characterisation and interpretation of genotypic data. The smart application of exome analysis to dementia patients, with a pre-analytical selection on familial, clinical, and instrumental features, improves the diagnostic yield of genetic test, reduces time for diagnosis, and allows a rapid and personalised management of disease.
痴呆症是一组复杂的神经退行性疾病，其特征在于不同但通常重叠的病理途径。遗传学在很大程度上与痴呆症的发生或发病风险相关。分子技术的最新进展使得能够在短时间内分析多个基因，但解释分析因多种因素而变得复杂：神经退行性疾病的临床复杂性、合并症的频率以及遗传疾病的高表型异质性。遗传咨询支持诊断过程，提供患者准确的家族和表型特征。在本综述中，我们总结了神经退行性痴呆症及其遗传决定因素。遗传变异和相关表型将分为高影响和低影响，以反映多因素和孟德尔遗传因素之间的病理连续性。此外，我们报告了与伴有认知障碍的神经退行性疾病相关基因的分子特征。特别是，痴呆症基因中罕见编码遗传变异的高频率有力地支持了遗传学家在临床表型特征描述和基因型数据解释方面的作用。对痴呆症患者进行外显子组分析的明智应用，在家族、临床和仪器特征方面进行分析前选择，可提高基因检测的诊断率，缩短诊断时间，并实现疾病的快速个性化管理。
