Next-generation sequencing reveals substantial genetic contribution to dementia with Lewy bodies.
Next-generation sequencing reveals substantial genetic contribution to dementia with Lewy bodies.
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DOI：
10.1016/j.nbd.2016.06.004
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发表时间：
2016-10
影响因子：
6.1
通讯作者：
Scholz SW
中科院分区：
文献类型：
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作者：
Geiger JT;Ding J;Crain B;Pletnikova O;Letson C;Dawson TM;Rosenthal LS;Pantelyat A;Gibbs JR;Albert MS;Hernandez DG;Hillis AE;Stone DJ;Singleton AB;North American Brain Expression Consortium;Hardy JA;Troncoso JC;Scholz SW
路易体痴呆（DLB）是仅次于阿尔茨海默病的第二常见的神经退行性痴呆。尽管越来越多的遗传因素与这种使人衰弱的疾病相关，但可归因于特定遗传缺陷的病例比例尚不清楚。为了对先前与DLB相关的9个基因中的致病性错义突变和编码风险变异的频率及谱系进行全面分析，我们对111例经病理证实的DLB患者进行了外显子组测序。所有患者均为来自北美的白种人。将所识别的错义突变的等位基因频率与222个对照外显子组进行了比较。值得注意的是，约25%的病例在APP、GBA或PSEN1中携带致病性突变或风险变异，这突出表明遗传缺陷在这种常见的神经退行性疾病的发病机制中起着核心作用。在我们的队列中，总计13%的患者在GBA中携带致病性突变，10%的病例在PSEN1中携带风险变异或突变，2%被发现携带APP突变。APOE ε4风险等位基因在DLB患者中显著过多（p值<0.001）。我们的结果确凿地表明，GBA、PSEN1和APP中的突变在DLB中很常见，应该考虑对诊断为路易体痴呆的患者进行基因检测。
DLB中GBA、PSEN1和APP致病性突变及风险变异的频率
Dementia with Lewy bodies (DLB) is the second most common neurodegenerative dementia after Alzheimer’s disease. Although an increasing number of genetic factors have been connected to this debilitating condition, the proportion of cases that can be attributed to distinct genetic defects is unknown. To provide a comprehensive analysis of the frequency and spectrum of pathogenic missense mutations and coding risk variants in nine genes previously implicated in DLB, we performed exome sequencing in 111 pathologically confirmed DLB patients. All patients were Caucasian individuals from North America. Allele frequencies of identified missense mutations were compared to 222 control exomes. Remarkably, ~25% of cases were found to carry a pathogenic mutation or risk variant in APP, GBA or PSEN1, highlighting that genetic defects play a central role in the pathogenesis of this common neurodegenerative disorder. In total, 13% of our cohort carried a pathogenic mutation in GBA, 10% of cases carried a risk variant or mutation in PSEN1, and 2% were found to carry an APP mutation. The APOE ε4 risk allele was significantly overrepresented in DLB patients (p-value <0.001). Our results conclusively show that mutations in GBA, PSEN1, and APP are common in DLB and consideration should be given to offer genetic testing to patients diagnosed with Lewy body dementia. Frequency of pathogenic mutations and risk variants in GBA, PSEN1 and APP in DLB