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Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series

Koriath, C., Kenny, J., Adamson, G., Druyeh, R., Taylor, W., Beck, J., Quinn, L., Mok, T. H., Dimitriadis, A., Norsworthy, P., Bass, N., Carter, J., Walker, Z., Kipps, C., Coulthard, E., Polke, J. M., Bernal-Quiros, M., Denning, N., Thomas, R., Raybould, R., Williams, J., Mummery, C. J., Wild, E. J., Houlden, H., Tabrizi, S. J., Rossor, M. N., Hummerich, H., Warren, J. D., Rowe, J. B., Rohrer, J. D., Schott, J. M., Fox, N. C., Collinge, J. and Mead, S. 2020. Predictors for a dementia gene mutation based on gene-panel next-generation sequencing of a large dementia referral series. Molecular Psychiatry 25 , pp. 3399-3412. 10.1038/s41380-018-0224-0

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Next-generation genetic sequencing (NGS) technologies facilitate the screening of multiple genes linked to neurodegenerative dementia, but there are few reports about their use in clinical practice. Which patients would most profit from testing, and information on the likelihood of discovery of a causal variant in a clinical syndrome, are conspicuously absent from the literature, mostly for a lack of large-scale studies. We applied a validated NGS dementia panel to 3241 patients with dementia and healthy aged controls; 13,152 variants were classified by likelihood of pathogenicity. We identified 354 deleterious variants (DV, 12.6% of patients); 39 were novel DVs. Age at clinical onset, clinical syndrome and family history each strongly predict the likelihood of finding a DV, but healthcare setting and gender did not. DVs were frequently found in genes not usually associated with the clinical syndrome. Patients recruited from primary referral centres were compared with those seen at higher-level research centres and a national clinical neurogenetic laboratory; rates of discovery were comparable, making selection bias unlikely and the results generalisable to clinical practice. We estimated penetrance of DVs using large-scale online genomic population databases and found 71 with evidence of reduced penetrance. Two DVs in the same patient were found more frequently than expected. These data should provide a basis for more informed counselling and clinical decision making.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Medicine
MRC Centre for Neuropsychiatric Genetics and Genomics (CNGG)
Additional Information: Open Access This article is licensed under a Creative Commons Attribution 4.0 International License
Publisher: Nature Publishing Group
ISSN: 1359-4184
Date of First Compliant Deposit: 19 October 2018
Date of Acceptance: 18 July 2018
Last Modified: 07 Jan 2021 14:36

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