TY - JOUR
T1 - Rare genetic variant in SORL1 may increase penetrance of Alzheimer's disease in a family with several generations of APOE-ϵ4 homozygosity
AU - Louwersheimer, Eva
AU - Cohn-Hokke, Petra E.
AU - Pijnenburg, Yolande A.L.
AU - Weiss, Marjan M.
AU - Sistermans, Erik A.
AU - Rozemuller, Annemieke J.
AU - Hulsman, Marc
AU - Van Swieten, John C.
AU - Van Duijn, Cock M.
AU - Barkhof, Frederik
AU - Koenei, Teddy
AU - Scheltens, Philip
AU - Van DerFlier, Wiesje M.
AU - Holstege, Henne
AU - Koene, Teddy
AU - Van der Flier, Wiesje M
PY - 2017
Y1 - 2017
N2 - Background: The major genetic risk factor for late onset Alzheimer's disease (AD) is theAPOE-ϵ4 allele. However,APOE-ϵ4 homozygosity is not fully penetrant, suggesting co-occurrence of additional genetic variants. Objective: To identify genetic factors that, next to APOE-ϵ4 homozygosity, contribute to the development of AD. Methods: We identified a family with nine AD patients spanning four generations, with an inheritance pattern suggestive of autosomal dominant AD, with no variants in PSEN1, PSEN2, or APP. We collected DNA from four affected and seven unaffected family members and performed exome sequencing on DNA from three affected and one unaffected family members. Results: All affected family members were homozygous for the APOE-ϵ4 allele. Statistical analysis revealed that AD onset in this family was significantly earlier than could be expected based on APOE genotype and gender. Next to APOE-ϵ4 homozygosity, we found that all four affected family members carried a rare variant in the VPS10 domain of the SORL1 gene, associated with APP processing and AD risk. Furthermore, three of four affected family members carried a rare variant in the TSHZ3 gene, also associated with APP processing. Affected family members presented between 61 and 74 years, with variable presence of microbleeds/cerebral amyloid angiopathy and electroencephalographic abnormalities. 1These authors contributed equally to this work. Conclusion:We hypothesize that next to APOE-ϵ4 homozygosity, impaired SORL1 protein function, and possibly impaired TSHZ3 function, further disturbed Aprocessing. The convergence of these genetic factors over several generations might clarify the increased AD penetrance and the autosomal dominant-like inheritance pattern of AD as observed in this family.
AB - Background: The major genetic risk factor for late onset Alzheimer's disease (AD) is theAPOE-ϵ4 allele. However,APOE-ϵ4 homozygosity is not fully penetrant, suggesting co-occurrence of additional genetic variants. Objective: To identify genetic factors that, next to APOE-ϵ4 homozygosity, contribute to the development of AD. Methods: We identified a family with nine AD patients spanning four generations, with an inheritance pattern suggestive of autosomal dominant AD, with no variants in PSEN1, PSEN2, or APP. We collected DNA from four affected and seven unaffected family members and performed exome sequencing on DNA from three affected and one unaffected family members. Results: All affected family members were homozygous for the APOE-ϵ4 allele. Statistical analysis revealed that AD onset in this family was significantly earlier than could be expected based on APOE genotype and gender. Next to APOE-ϵ4 homozygosity, we found that all four affected family members carried a rare variant in the VPS10 domain of the SORL1 gene, associated with APP processing and AD risk. Furthermore, three of four affected family members carried a rare variant in the TSHZ3 gene, also associated with APP processing. Affected family members presented between 61 and 74 years, with variable presence of microbleeds/cerebral amyloid angiopathy and electroencephalographic abnormalities. 1These authors contributed equally to this work. Conclusion:We hypothesize that next to APOE-ϵ4 homozygosity, impaired SORL1 protein function, and possibly impaired TSHZ3 function, further disturbed Aprocessing. The convergence of these genetic factors over several generations might clarify the increased AD penetrance and the autosomal dominant-like inheritance pattern of AD as observed in this family.
KW - APOE
KW - Alzheimer's disease
KW - Genetics
KW - Penetrance
KW - SORL1
UR - http://www.scopus.com/inward/record.url?scp=85024397373&partnerID=8YFLogxK
U2 - https://doi.org/10.3233/JAD-160091
DO - https://doi.org/10.3233/JAD-160091
M3 - Article
C2 - 27911290
SN - 1387-2877
VL - 56
SP - 63
EP - 74
JO - Journal of Alzheimer's Disease
JF - Journal of Alzheimer's Disease
IS - 1
ER -