title: Exome sequencing in dementia with Lewy bodies.
abstract: 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.
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: M J
authors.initials: MJ
authors.lastname: Keogh
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: M
authors.initials: M
authors.lastname: Kurzawa-Akanbi
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: H
authors.initials: H
authors.lastname: Griffin
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: K
authors.initials: K
authors.lastname: Douroudis
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: K L
authors.initials: KL
authors.lastname: Ayers
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: R I
authors.initials: RI
authors.lastname: Hussein
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: G
authors.initials: G
authors.lastname: Hudson
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: A
authors.initials: A
authors.lastname: Pyle
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: H J
authors.initials: HJ
authors.lastname: Cordell
authors.affiliation: NIHR Biomedical Research Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Campus for Ageing and Vitality, Newcastle upon Tyne, UK.|Institute for Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: J
authors.initials: J
authors.lastname: Attems
authors.affiliation: NIHR Biomedical Research Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Campus for Ageing and Vitality, Newcastle upon Tyne, UK.|Institute for Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: I G
authors.initials: IG
authors.lastname: McKeith
authors.affiliation: NIHR Biomedical Research Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Campus for Ageing and Vitality, Newcastle upon Tyne, UK.|Institute for Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: J T
authors.initials: JT
authors.lastname: O'Brien
authors.affiliation: NIHR Biomedical Research Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Campus for Ageing and Vitality, Newcastle upon Tyne, UK.|Institute for Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: D J
authors.initials: DJ
authors.lastname: Burn
authors.affiliation: NIHR Biomedical Research Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Campus for Ageing and Vitality, Newcastle upon Tyne, UK.|Institute for Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: C M
authors.initials: CM
authors.lastname: Morris
authors.affiliation: NIHR Biomedical Research Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Campus for Ageing and Vitality, Newcastle upon Tyne, UK.|Institute for Neuroscience, The Medical School, Newcastle University, Newcastle upon Tyne, UK.
authors.forename: A J
authors.initials: AJ
authors.lastname: Thomas
authors.affiliation: Institute of Genetic Medicine, Newcastle University, Newcastle upon Tyne, UK.|NIHR Biomedical Research Unit, Newcastle upon Tyne Hospitals NHS Foundation Trust, Campus for Ageing and Vitality, Newcastle upon Tyne, UK.
authors.forename: P F
authors.initials: PF
authors.lastname: Chinnery
mesh_terms: D000368:Aged; D059472:Exome / Q000235:genetics*; D005260:Female; D006801:Humans; D020961:Lewy Body Disease / Q000235:genetics*; D008297:Male
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