RESUMO
BACKGROUND: 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. METHODS: 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. RESULTS: 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. CONCLUSION: 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.