Exome sequencing in dementia with Lewy bodies

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...

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Published in:Translational psychiatry 2016-02, Vol.6 (2), p.e728-e728
Main Authors: Keogh, M J, Kurzawa-Akanbi, M, Griffin, H, Douroudis, K, Ayers, K L, Hussein, R I, Hudson, G, Pyle, A, Cordell, H J, Attems, J, McKeith, I G, O'Brien, J T, Burn, D J, Morris, C M, Thomas, A J, Chinnery, P F
Format: Article
Language:English
Subjects:
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Behavioral Sciences
Biological Psychology
Dementia
Exome - genetics
Female
Humans
Lewy Body Disease - genetics
Male
Medicine
Medicine & Public Health
Neurosciences
Original
original-article
Pharmacotherapy
Psychiatry
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Summary: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 ɛ4 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 ɛ4 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.
ISSN:2158-3188
2158-3188
DOI:10.1038/tp.2015.220