Analysis of known amyotrophic lateral sclerosis and frontotemporal dementia genes reveals a substantial genetic burden in patients manifesting both diseases not carrying the C9orf72 expansion mutation
Analysis of known amyotrophic lateral sclerosis and frontotemporal dementia genes reveals a substantial genetic burden in patients manifesting both diseases not carrying the C9orf72 expansion mutation
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DOI：
10.1136/jnnp-2017-316820
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发表时间：
2018-02-01
影响因子：
11
通讯作者：
Clarimon, Jordi
中科院分区：
文献类型：
--
作者：
Dols-Icardo, Oriol;Garcia-Redondo, Alberto;Clarimon, Jordi
肌萎缩侧索硬化症(ALS)和额颞叶痴呆(FTD)是临床、病理和遗传学的一部分。目的本研究的目的是评估ALS和FTD(ALS/FTD)合并ALS和FTD(ALS/FTD)患者的突变负担，这是导致ALS和FTD的最重要的遗传原因。我们的最后一组研究包括54例临床诊断为ALS/FTD的患者(16例死后神经病理诊断有效)。结果发现11例患者可能携带致病突变，总突变频率为20.4%。TBK1是ALS/FTD最重要的遗传原因(n=5；9.3%)。第二个最常见的突变基因是SQSTM1，有三个突变携带者(其中一个还含有TBK1突变)。我们还检测了TAF15、VCP和TARDBP可能的致病基因改变以及FIG4和ERBB4可能的致病突变。结论ALS和FTD并存存在较高的遗传负担，并将TAF15、FIG4和ERBB4的表型扩展到FTD。系统筛查ALS和FTD基因可用于既有C9orf72扩增突变又无C9orf72扩增突变的患者，而不考虑其家族病史。
Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are part of a clinical, pathological and genetic continuum.Objectives The purpose of the present study was to assess the mutation burden that is present in patients with concurrent ALS and FTD (ALS/FTD) not carrying the chromosome 9 open reading frame 72 (C9orf72) hexanucleotide repeat expansion, the most important genetic cause in both diseases.Methods From an initial group of 973 patients with ALS, we retrospectively selected those patients fulfilling diagnostic criteria of concomitant ALS and FTD lacking the repeat expansion mutation in C9orf72. Our final study group consisted of 54 patients clinically diagnosed with ALS/FTD (16 with available postmortem neuropathological diagnosis). Data from whole exome sequencing were used to screen for mutations in known ALS and/or FTD genes.Results We identified 11 patients carrying a probable pathogenic mutation, representing an overall mutation frequency of 20.4%. TBK1 was the most important genetic cause of ALS/FTD (n=5; 9.3%). The second most common mutated gene was SQSTM1, with three mutation carriers (one of them also harboured a TBK1 mutation). We also detected probable pathogenic genetic alterations in TAF15, VCP and TARDBP and possible pathogenic mutations in FIG4 and ERBB4.Conclusion Our results indicate a high genetic burden underlying the co-occurrence of ALS and FTD and expand the phenotype associated with TAF15, FIG4 and ERBB4 to FTD. A systematic screening of ALS and FTD genes could be indicated in patients manifesting both diseases without the C9orf72 expansion mutation, regardless of family history of disease.