背景：由于尚未描述的染色体重排，早期发作的常染色体显性遗传阿尔茨海默病（EOADAD）的有症状和无症状携带者的临床特征可能会增加有关阿尔茨海默病的现有知识，并可能启发新的和修饰基因。我们报告了携带新型APP重复重排的无症状和有症状个体的临床和遗传特征。
方法：招募了一个具有家族性认知功能减退或脑出血的7代家系个体。参与者接受了医疗，神经学,和神经心理学评估。遗传分析包括染色体微阵列，核型,荧光原位杂交,和全基因组测序。
结果：在68个人中，六位女性患有痴呆症，四名男性出现脑出血。其中,发现9个染色体21拷贝数增加（chr21：27,224,097-27,871,284，GRCh37/hg19），包括APP基因座（APP-dup）。在七,染色体5拷贝数增加（Chr5：24,786,234-29,446,070，GRCh37/hg19）（Chr5-CNG）与APP-dup分离。两个重复共同定位在染色体18q21.1上，并在25个症状前携带者中分离。与非运营商相比，无症状携带者在30多岁时表现出认知能力下降。三分之一的受影响个体诊断为非免疫疾病。
结论：APP额外剂量，即使是孤立的，当位于21号染色体之外时，也是致病的。APP重复的临床表现各不相同，可能具有性别特异性，即，男性ICH和女性认知行为恶化。与免疫疾病的关联目前尚不清楚，但可能被证明是相关的。Chr5-CNG共分离和周围18号染色体遗传序列的含义需要进一步澄清。
The clinical characteristics of symptomatic and asymptomatic carriers of early- onset autosomal dominant Alzheimer\'s (EOADAD) due to a yet-undescribed chromosomal rearrangement may add to the available body of knowledge about Alzheimer\'s disease and may enlighten novel and modifier genes. We report the clinical and genetic characteristics of asymptomatic and symptomatic individuals carrying a novel APP duplication rearrangement.
Individuals belonging to a seven-generation pedigree with familial cognitive decline or intracerebral hemorrhages were recruited. Participants underwent medical, neurological, and neuropsychological evaluations. The genetic analysis included chromosomal microarray, Karyotype, fluorescence in situ hybridization, and whole genome sequencing.
Of 68 individuals, six females presented with dementia, and four males presented with intracerebral hemorrhage. Of these, nine were found to carry Chromosome 21 copy number gain (chr21:27,224,097-27,871,284, GRCh37/hg19) including the APP locus (APP-dup). In seven, Chromosome 5 copy number gain (Chr5: 24,786,234-29,446,070, GRCh37/hg19) (Chr5-CNG) cosegregated with the APP-dup. Both duplications co-localized to chromosome 18q21.1 and segregated in 25 pre-symptomatic carriers. Compared to non-carriers, asymptomatic carriers manifested cognitive decline in their mid-thirties. A third of the affected individuals carried a diagnosis of a dis-immune condition.
APP extra dosage, even in isolation and when located outside chromosome 21, is pathogenic. The clinical presentation of APP duplication varies and may be gender specific, i.e., ICH in males and cognitive-behavioral deterioration in females. The association with immune disorders is presently unclear but may prove relevant. The implication of Chr5-CNG co-segregation and the surrounding chromosome 18 genetic sequence needs further clarification.
