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Exome sequencing in dementia with Lewy bodies

Lookup NU author(s): Dr Michael Keogh, Dr Marzena Kurzawa-Akanbi, Dr Helen GriffinORCiD, Dr Konstantinos Douroudis, Dr Kristin Ayers, Professor Gavin Hudson, Dr Angela Pyle, Professor Heather Cordell, Professor Johannes Attems, Professor Ian McKeith, Professor John O'Brien, Professor David Burn, Dr Christopher Morris, Professor Alan ThomasORCiD, Professor Patrick Chinnery



This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).


Dementia with Lewy bodies (DLB) is the second most common form of degenerative dementia. Siblings of affected individuals are at greater risk of developing DLB, but little is known about the underlying genetic basis of the disease. We set out to determine whether mutations in known highly penetrant neurodegenerative disease genes are found in patients with DLB. Whole-exome sequencing was performed on 91 neuropathologically confirmed cases of DLB, supplemented by independent APOE genotyping. Genetic variants were classified using established criteria, and additional neuropathological examination was performed for putative mutation carriers. Likely pathogenic variants previously described as causing monogenic forms of neurodegenerative disease were found in 4.4% of patients with DLB. The APOE epsilon 4 allele increased the risk of disease (P = 0.0001), conferred a shorter disease duration (P = 0.043) and earlier age of death (P = 0.0015). In conclusion, although known pathogenic mutations in neurodegenerative disease genes are uncommon in DLB, known genetic risk factors are present in >60% of cases. APOE e4 not only modifies disease risk, but also modulates the rate of disease progression. The reduced penetrance of reported pathogenic alleles explains the lack of a family history in most patients, and the presence of variants previously described as causing frontotemporal dementia suggests a mechanistic overlap between DLB and other neurodegenerative diseases.

Publication metadata

Author(s): Keogh MJ, Kurzawa-Akanbi M, Griffin H, Douroudis K, Ayers KL, Hussein RI, Hudson G, Pyle A, Cordell HJ, Attems J, McKeith IG, O'Brien JT, Burn DJ, Morris CM, Thomas AJ, Chinnery PF

Publication type: Article

Publication status: Published

Journal: Translational Psychiatry

Year: 2016

Volume: 6

Print publication date: 01/02/2016

Online publication date: 02/02/2016

Acceptance date: 13/11/2015

Date deposited: 14/06/2016

ISSN (electronic): 2158-3188

Publisher: Nature Publishing Group


DOI: 10.1038/tp.2015.220


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