Department of Neurology, Genetics and Aging Research Unit, MassGeneral Institute for Neurodegenerative Disease, Massachusetts General Hospital, Charlestown, MA, USA.
Department of Information Engineering, University of Brescia, Brescia, Italy.
Mol Psychiatry. 2014 Jun;19(6):676-81. doi: 10.1038/mp.2013.77. Epub 2013 Jun 11.
Over 200 rare and fully penetrant pathogenic mutations in amyloid precursor protein (APP), presenilin 1 and 2 (PSEN1 and PSEN2) cause a subset of early-onset familial Alzheimer's disease (EO-FAD). Of these, 21 cases of EO-FAD families carrying unique APP locus duplications remain the only pathogenic copy number variations (CNVs) identified to date in Alzheimer's disease (AD). Using high-density DNA microarrays, we performed a comprehensive genome-wide analysis for the presence of rare CNVs in 261 EO-FAD and early/mixed-onset pedigrees. Our analysis revealed 10 novel private CNVs in 10 EO-FAD families overlapping a set of genes that includes: A2BP1, ABAT, CDH2, CRMP1, DMRT1, EPHA5, EPHA6, ERMP1, EVC, EVC2, FLJ35024 and VLDLR. In addition, CNVs encompassing two known frontotemporal dementia genes, CHMP2B and MAPT were found. To our knowledge, this is the first study reporting rare gene-rich CNVs in EO-FAD and early/mixed-onset AD that are likely to underlie pathogenicity in familial AD and perhaps related dementias.
超过 200 种罕见且完全外显的淀粉样前体蛋白（APP）、早老素 1 和 2（PSEN1 和 PSEN2）致病性突变可导致一小部分早发性家族性阿尔茨海默病（EO-FAD）。在这些突变中，携带 APP 基因座重复的 21 例 EO-FAD 家族是迄今为止在阿尔茨海默病（AD）中发现的唯一致病性拷贝数变异（CNV）。使用高密度 DNA 微阵列，我们对 261 个 EO-FAD 和早发性/混合性发病家系进行了罕见 CNV 的全基因组综合分析。我们的分析在 10 个 EO-FAD 家族中发现了 10 个新的个体 CNV，这些 CNV 重叠了一组基因，包括：A2BP1、ABAT、CDH2、CRMP1、DMRT1、EPHA5、EPHA6、ERMP1、EVC、EVC2 和 VLDLR。此外，还发现了包含两个已知额颞叶痴呆基因 CHMP2B 和 MAPT 的 CNV。据我们所知，这是第一项报道 EO-FAD 和早发性/混合性 AD 中罕见基因丰富的 CNV 的研究，这些 CNV 可能是家族性 AD 及相关痴呆症的致病原因。
