APP, PSEN1, and PSEN2 mutations in early-onset Alzheimer disease: A genetic screening study of familial and sporadic cases

BackgroundAmyloid protein precursor (APP), presenilin-1 (PSEN1), and presenilin-2 (PSEN2) mutations cause autosomal dominant forms of early-onset Alzheimer disease (AD-EOAD). Although these genes were identified in the 1990s, variant classification remains a challenge, highlighting the need to colligate mutations from large series.Methods and findingsWe report here a novel update (2012–2016) of the genetic screening of the large AD-EOAD series ascertained across 28 French hospitals from 1993 onwards, bringing the total number of families with identified mutations to n = 170. Families were included when at least two first-degree relatives suffered from early-onset Alzheimer disease (EOAD) with an age of onset (AOO) ≤65 y in two generations. Furthermore, we also screened 129 sporadic cases of Alzheimer disease with an AOO below age 51 (44% males, mean AOO = 45 ± 2 y). APP, PSEN1, or PSEN2 mutations were identified in 53 novel AD-EOAD families. Of the 129 sporadic cases screened, 17 carried a PSEN1 mutation and 1 carried an APP duplication (13%). Parental DNA was available for 10 sporadic mutation carriers, allowing us to show that the mutation had occurred de novo in each case. Thirteen mutations (12 in PSEN1 and 1 in PSEN2) identified either in familial or in sporadic cases were previously unreported. Of the 53 mutation carriers with available cerebrospinal fluid (CSF) biomarkers, 46 (87%) had all three CSF biomarkers—total tau protein (Tau), phospho-tau protein (P-Tau), and amyloid β (Aβ)42—in abnormal ranges. No mutation carrier had the three biomarkers in normal ranges. One limitation of this study is the absence of functional assessment of the possibly and probably pathogenic variants, which should help their classification.ConclusionsOur findings suggest that a nonnegligible fraction of PSEN1 mutations occurs de novo, which is of high importance for genetic counseling, as PSEN1 mutational screening is currently performed in familial cases only. Among the 90 distinct mutations found in the whole sample of families and isolated cases, definite pathogenicity is currently established for only 77%, emphasizing the need to pursue the effort to classify variants.背景 淀粉样蛋白前体（APP）、早老素1（PSEN1）及早老素2（PSEN2）的突变可引发常染色体显性遗传早发性阿尔茨海默病（AD-EOAD）。尽管上述基因已于20世纪90年代被鉴定，但变异体分类仍是一项临床与科研挑战，凸显出对大规模整合突变数据集的迫切需求。方法与结果 本文报道了自1993年起，针对法国28家医院招募的大型AD-EOAD队列开展的2012-2016年基因筛查更新结果，使携带明确致病突变的家族总数增至170个。本研究的家族纳入标准为：至少两代家族中存在至少2名一级亲属罹患早发性阿尔茨海默病，且发病年龄（AOO）≤65岁。此外，本研究还筛查了129例发病年龄低于51岁的阿尔茨海默病散发病例（男性占比44%，平均发病年龄为45±2岁）。最终在53个新发现的AD-EOAD家族中鉴定出APP、PSEN1或PSEN2突变。在129例筛查的散发病例中，17例携带PSEN1突变，1例携带APP基因重复突变（占比13%）。研究获取了10例散发性突变携带者的亲本DNA，通过检测证实所有突变均为新发突变。在家族性或散发性病例中鉴定出的13个突变（其中PSEN1含12个，PSEN2含1个）此前均未见文献报道。在53例具备脑脊液（CSF）生物标志物检测数据的突变携带者中，46例（87%）的三项核心生物标志物——总tau蛋白（Tau）、磷酸化tau蛋白（P-Tau）及β淀粉样蛋白42（Aβ42）——均处于异常范围，无1例携带者的三项生物标志物均处于正常区间。本研究存在一项局限性：未对疑似及可能致病变异体开展功能验证，而此类验证将有助于推进变异体的分类工作。结论 本研究结果提示，相当比例的PSEN1突变为新发突变，这一发现对遗传咨询具有重要指导价值，因为当前PSEN1突变筛查仅在家族性病例中开展。在整个研究队列（包括家族病例与散发病例）中发现的90个不同突变里，目前仅77%被明确确认具有致病性，这凸显出持续推进变异体分类工作的必要性。