■行为变异额颞叶痴呆(bvFTD)是一种具有高度遗传的临床异质性综合征。然而,与bvFTD相关的突变频率尚未确定。本研究的目的是调查具有遗传bvFTD变异的中国汉族患者的频率。
■从我们的额颞叶变性数据库中选择的49名bvFTD患者,2014年7月至2019年12月在宣武医院连续招募了14例属于8个家庭的家庭病例和35例散发病例(北京,中国)。进行全外显子组测序(WES)并使用重复引发的PCR来测试样品的C9orf72六核苷酸重复扩增突变。分析了遗传变异的频率和新变异的致病性。
■在17例bvFTD患者中发现了10种致病或可能的致病变体,包括C9orf72重复扩展,六个先前报道的突变和三个新突变(MAPTp.R5C,p.D54N,GRNp.P451L)。基因突变占病例总数的27.9%(12/43),87.5%(7/8)的家族性bvFTD患者,和14.3%(5/35)与零星bvFTD。致病变异主要发生在MAPT基因(20.9%,9/43),其次是C9orf72重复扩增(2.3%,1/43),GRN基因(2.3%,1/43)和FUS基因(2.3%,1/43).
■中国bvFTD患者的遗传变异率很高,强调bvFTD基因检测的必要性。
BACKGROUND: Behavioral variant frontotemporal dementia (bvFTD) is a clinically heterogeneous syndrome with high heredity. However, the frequencies of mutations associated with bvFTD have yet to be determined. The aim of the current study was to investigate the frequency of Chinese Han patients harboring genetic bvFTD variants.
METHODS: A total of 49 bvFTD patients selected from our frontotemporal lobar degeneration database, including 14 familial cases belonging to eight families and 35 sporadic cases were consecutively recruited from July 2014 to December 2019 at Xuanwu Hospital (Beijing, China). Whole-exome sequencing (WES) was performed and repeat-primed PCR was used to test samples for the C9orf72 hexanucleotide repeat expansion mutation. The frequency of genetic variants and the pathogenicity of the novel variants were analyzed.
RESULTS: Ten pathogenic or likely pathogenic variants were identified in 17 bvFTD patients, including C9orf72 repeat expansions, six previously reported mutations and three novel mutations (MAPT p. R5C, p. D54N, GRN p. P451L). Genetic mutations accounted for 27.9% (12/43) of total cases, 87.5% (7/8) of patients with familial bvFTD, and 14.3% (5/35) with sporadic bvFTD. Pathogenic variants mostly occurred in MAPT gene (20.9%, 9/43), followed by C9orf72 repeat expansions (2.3%, 1/43), GRN gene (2.3%, 1/43) and FUS gene (2.3%, 1/43).
CONCLUSIONS: There was a high prevalence of genetic variants in Chinese bvFTD patients, highlighting the necessity of genetic testing for bvFTD.