Genetic diagnosis of dementia by next-generation sequencing

Early diagnosis of dementia is essential for the instigation of the best treatment regime. This is, however, notoriously difficult, as changes begin occurring many years before any symptoms may be apparent. Identification of a specific genetic cause of early onset dementia (EOD) is important but can be difficult because of pleiotropy, locus heterogeneity and accessibility of gene tests. In this study, the authors assessed the use of next-generation sequencing (NGS) technologies as a quick, accurate and cost effective method for determining a genetic diagnosis in EOD. Gene panel-based technologies were developed to assess 16 genes known to contain dementia-causing mutations and were combined with PCR-based assessments of the C9orf72 hexanucleotide repeat expansion and the octapeptide repeat region of PRNP, the prion protein gene. In a blinded study of 95 samples, very high sensitivity and specificity were shown to be achievable using either Ion Torrent or MiSeq sequencing platforms. Modifications to the gene panel permit accurate detection of structural variation in the amyloid precursor protein, APP. In 2/10 samples which had been selected because they possess a variant of uncertain significance the new technology discovered a causal mutation in genes not previously sequenced. A large proportion (23/85) of samples showed genetic variants of uncertain significance in addition to known mutations. Gene panels, such as this one from the Medical Research Council, UK, and similar technologies are likely to transform the diagnosis of early onset dementia diagnosis, significantly impacting the proportion of patients in whom a genetic cause is identified.

Beck J, et al. Neurobiol Aging 2013; PII: S0197-4580(13)00322-9