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Mol Psychiatry. 2018 Oct 2. doi: 10.1038/s41380-018-0224-0. [Epub ahead of print]

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

Author information

1
MRC Prion Unit at UCL, UCL Institute of Prion Diseases, Courtauld Building, London, W1W 7FF, UK.
2
UCL Division of Psychiatry, Maple House, University College London, London, UK.
3
Essex Partnership University NHS Foundation Trust, Essex, SS11 7XX, UK.
4
Wessex Neurological Centre, University Hospital Southampton NHS Foundation Trust, Southampton, UK.
5
Institute of Clinical Neuroscience, University of Bristol, Level 1 Learning and Research Building, Bristol, BS10 5NB, UK.
6
Neurogenetics Laboratory, National Hospital for Neurology and Neurosurgery, Queen Square, London, WC1N 3BG, UK.
7
Division of Psychological Medicine & Clinical Neurosciences, Cardiff University, Hadyn Ellis Building, Maindy Road, Cardiff, CF24 4HQ, UK.
8
Dementia Research Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
9
Huntington's Disease Centre, Department of Neurodegenerative Disease, UCL Institute of Neurology, Queen Square, London, WC1N 3BG, UK.
10
Department of Clinical Neurosciences, University of Cambridge, Cambridge, CB2 0SZ, UK.
11
Medical Research Council Cognition and Brain Sciences Unit, Cambridge, CB2 7EF, UK.
12
MRC Prion Unit at UCL, UCL Institute of Prion Diseases, Courtauld Building, London, W1W 7FF, UK. s.mead@prion.ucl.ac.uk.

Abstract

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.

PMID:
30279455
DOI:
10.1038/s41380-018-0224-0

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