A de novo, mosaic and complex chromosome 21 rearrangement causes APP triplication and familial autosomal dominant early onset Alzheimer disease
Abstract Copy number variation (CNV) of the amyloid-β precursor protein gene (APP) is a known cause of autosomal dominant Alzheimer disease (ADAD), but de novo genetic variants causing ADAD are rare. We report a mother and daughter with neuropathologically confirmed definite Alzheimer disease (AD) a...
Saved in:
| Main Authors: | , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-01-01
|
| Series: | Scientific Reports |
| Subjects: | |
| Online Access: | https://doi.org/10.1038/s41598-025-86645-0 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1850225932407668736 |
|---|---|
| author | Emma Ehn Jesper Eisfeldt Jose M. Laffita-Mesa Håkan Thonberg Jacqueline Schoumans Anne M. Portaankorva Matti Viitanen Anna Lindstrand Inger Nennesmo Caroline Graff |
| author_facet | Emma Ehn Jesper Eisfeldt Jose M. Laffita-Mesa Håkan Thonberg Jacqueline Schoumans Anne M. Portaankorva Matti Viitanen Anna Lindstrand Inger Nennesmo Caroline Graff |
| author_sort | Emma Ehn |
| collection | DOAJ |
| description | Abstract Copy number variation (CNV) of the amyloid-β precursor protein gene (APP) is a known cause of autosomal dominant Alzheimer disease (ADAD), but de novo genetic variants causing ADAD are rare. We report a mother and daughter with neuropathologically confirmed definite Alzheimer disease (AD) and extensive cerebral amyloid angiopathy (CAA). Copy number analysis identified an increased number of APP copies and genome sequencing (GS) revealed the underlying complex genomic rearrangement (CGR) including a triplication of APP with two unique breakpoint junctions (BPJs). The mosaic state in the mother had likely occurred de novo. Digital droplet PCR (ddPCR) on 42 different tissues, including 17 different brain regions, showed the derivative chromosome at varying mosaic levels (20–96%) in the mother who had symptom onset at age 58 years. In contrast, the derivative chromosome was present in all analyzed cells in the daughter whose symptom onset was at 34 years. This study reveals the architecture of a de novo CGR causing APP triplication and ADAD with a striking difference in age at onset between the fully heterozygous daughter compared to the mosaic mother. The GS analysis identified the complexity of the CGR illustrating its usefulness in identifying structural variants (SVs) in neurodegenerative disorders. |
| format | Article |
| id | doaj-art-2bc3e75a4480464bb22b59f8f0a080ff |
| institution | OA Journals |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-2bc3e75a4480464bb22b59f8f0a080ff2025-08-20T02:05:13ZengNature PortfolioScientific Reports2045-23222025-01-0115111410.1038/s41598-025-86645-0A de novo, mosaic and complex chromosome 21 rearrangement causes APP triplication and familial autosomal dominant early onset Alzheimer diseaseEmma Ehn0Jesper Eisfeldt1Jose M. Laffita-Mesa2Håkan Thonberg3Jacqueline Schoumans4Anne M. Portaankorva5Matti Viitanen6Anna Lindstrand7Inger Nennesmo8Caroline Graff9Division for Neurogeriatrics, Centre for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska InstitutetDepartment for Molecular Medicine and Surgery, Karolinska InstitutetDivision for Neurogeriatrics, Centre for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska InstitutetDepartment for Molecular Medicine and Surgery, Karolinska InstitutetDépartement de Médicine de Laboratoire et Pathologie, Centre Universitaire Hospitalier Vaudois (CHUV)Faculty of Medicine, Clinical Neurosciences, University of HelsinkiDivision for Clinical Geriatrics, Department of Neurobiology, Care Sciences and Society, Karolinska InstitutetDepartment for Molecular Medicine and Surgery, Karolinska InstitutetDepartment of Oncology-Pathology, Karolinska InstitutetDivision for Neurogeriatrics, Centre for Alzheimer Research, Department of Neurobiology, Care Sciences and Society, Karolinska InstitutetAbstract Copy number variation (CNV) of the amyloid-β precursor protein gene (APP) is a known cause of autosomal dominant Alzheimer disease (ADAD), but de novo genetic variants causing ADAD are rare. We report a mother and daughter with neuropathologically confirmed definite Alzheimer disease (AD) and extensive cerebral amyloid angiopathy (CAA). Copy number analysis identified an increased number of APP copies and genome sequencing (GS) revealed the underlying complex genomic rearrangement (CGR) including a triplication of APP with two unique breakpoint junctions (BPJs). The mosaic state in the mother had likely occurred de novo. Digital droplet PCR (ddPCR) on 42 different tissues, including 17 different brain regions, showed the derivative chromosome at varying mosaic levels (20–96%) in the mother who had symptom onset at age 58 years. In contrast, the derivative chromosome was present in all analyzed cells in the daughter whose symptom onset was at 34 years. This study reveals the architecture of a de novo CGR causing APP triplication and ADAD with a striking difference in age at onset between the fully heterozygous daughter compared to the mosaic mother. The GS analysis identified the complexity of the CGR illustrating its usefulness in identifying structural variants (SVs) in neurodegenerative disorders.https://doi.org/10.1038/s41598-025-86645-0Autosomal dominant Alzheimer disease (ADAD)Amyloid-β precursor protein gene (APP)Cerebral amyloid angiopathy (CAA)Complex genomic rearrangement (CGR)MosaicismStructural variant (SV). |
| spellingShingle | Emma Ehn Jesper Eisfeldt Jose M. Laffita-Mesa Håkan Thonberg Jacqueline Schoumans Anne M. Portaankorva Matti Viitanen Anna Lindstrand Inger Nennesmo Caroline Graff A de novo, mosaic and complex chromosome 21 rearrangement causes APP triplication and familial autosomal dominant early onset Alzheimer disease Scientific Reports Autosomal dominant Alzheimer disease (ADAD) Amyloid-β precursor protein gene (APP) Cerebral amyloid angiopathy (CAA) Complex genomic rearrangement (CGR) Mosaicism Structural variant (SV). |
| title | A de novo, mosaic and complex chromosome 21 rearrangement causes APP triplication and familial autosomal dominant early onset Alzheimer disease |
| title_full | A de novo, mosaic and complex chromosome 21 rearrangement causes APP triplication and familial autosomal dominant early onset Alzheimer disease |
| title_fullStr | A de novo, mosaic and complex chromosome 21 rearrangement causes APP triplication and familial autosomal dominant early onset Alzheimer disease |
| title_full_unstemmed | A de novo, mosaic and complex chromosome 21 rearrangement causes APP triplication and familial autosomal dominant early onset Alzheimer disease |
| title_short | A de novo, mosaic and complex chromosome 21 rearrangement causes APP triplication and familial autosomal dominant early onset Alzheimer disease |
| title_sort | de novo mosaic and complex chromosome 21 rearrangement causes app triplication and familial autosomal dominant early onset alzheimer disease |
| topic | Autosomal dominant Alzheimer disease (ADAD) Amyloid-β precursor protein gene (APP) Cerebral amyloid angiopathy (CAA) Complex genomic rearrangement (CGR) Mosaicism Structural variant (SV). |
| url | https://doi.org/10.1038/s41598-025-86645-0 |
| work_keys_str_mv | AT emmaehn adenovomosaicandcomplexchromosome21rearrangementcausesapptriplicationandfamilialautosomaldominantearlyonsetalzheimerdisease AT jespereisfeldt adenovomosaicandcomplexchromosome21rearrangementcausesapptriplicationandfamilialautosomaldominantearlyonsetalzheimerdisease AT josemlaffitamesa adenovomosaicandcomplexchromosome21rearrangementcausesapptriplicationandfamilialautosomaldominantearlyonsetalzheimerdisease AT hakanthonberg adenovomosaicandcomplexchromosome21rearrangementcausesapptriplicationandfamilialautosomaldominantearlyonsetalzheimerdisease AT jacquelineschoumans adenovomosaicandcomplexchromosome21rearrangementcausesapptriplicationandfamilialautosomaldominantearlyonsetalzheimerdisease AT annemportaankorva adenovomosaicandcomplexchromosome21rearrangementcausesapptriplicationandfamilialautosomaldominantearlyonsetalzheimerdisease AT mattiviitanen adenovomosaicandcomplexchromosome21rearrangementcausesapptriplicationandfamilialautosomaldominantearlyonsetalzheimerdisease AT annalindstrand adenovomosaicandcomplexchromosome21rearrangementcausesapptriplicationandfamilialautosomaldominantearlyonsetalzheimerdisease AT ingernennesmo adenovomosaicandcomplexchromosome21rearrangementcausesapptriplicationandfamilialautosomaldominantearlyonsetalzheimerdisease AT carolinegraff adenovomosaicandcomplexchromosome21rearrangementcausesapptriplicationandfamilialautosomaldominantearlyonsetalzheimerdisease AT emmaehn denovomosaicandcomplexchromosome21rearrangementcausesapptriplicationandfamilialautosomaldominantearlyonsetalzheimerdisease AT jespereisfeldt denovomosaicandcomplexchromosome21rearrangementcausesapptriplicationandfamilialautosomaldominantearlyonsetalzheimerdisease AT josemlaffitamesa denovomosaicandcomplexchromosome21rearrangementcausesapptriplicationandfamilialautosomaldominantearlyonsetalzheimerdisease AT hakanthonberg denovomosaicandcomplexchromosome21rearrangementcausesapptriplicationandfamilialautosomaldominantearlyonsetalzheimerdisease AT jacquelineschoumans denovomosaicandcomplexchromosome21rearrangementcausesapptriplicationandfamilialautosomaldominantearlyonsetalzheimerdisease AT annemportaankorva denovomosaicandcomplexchromosome21rearrangementcausesapptriplicationandfamilialautosomaldominantearlyonsetalzheimerdisease AT mattiviitanen denovomosaicandcomplexchromosome21rearrangementcausesapptriplicationandfamilialautosomaldominantearlyonsetalzheimerdisease AT annalindstrand denovomosaicandcomplexchromosome21rearrangementcausesapptriplicationandfamilialautosomaldominantearlyonsetalzheimerdisease AT ingernennesmo denovomosaicandcomplexchromosome21rearrangementcausesapptriplicationandfamilialautosomaldominantearlyonsetalzheimerdisease AT carolinegraff denovomosaicandcomplexchromosome21rearrangementcausesapptriplicationandfamilialautosomaldominantearlyonsetalzheimerdisease |