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

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.

Fig. 1

Frequency of variant pathogenicity classes in the data set. This figure shows the frequency of the various variant pathogenicity classes in the total data set broken down by individual phenotypes

Fig. 2

Genes in which novel DVs were found. Eleven percent of DVs were not previously described in the literature (n = 39). Known mutations were found in PRNP (24.6%), C9orf72 (19.2%), MAPT (15.8%), GRN (9.9%), PSEN1 (9.6%), APP (3.4%), CSF1R (2.0%), VCP (1.7%), SQSTM1 (0.9%), TARDBP (0.6%) and CHMP2B, ITM2B, NOTCH3, PSEN2 and TREM2 (0.3% each)

Fig. 3

Chart illustrating the association between clinical syndrome and gene implicated. Numbers on the left refer to patients with clinical syndromes, numbers of the right refer to DVs in implicated genes

Fig. 4

Proportion of patients with a deleterious or likely deleterious variant per age group (%). The distribution is skewed towards the younger ages of onset, but we discovered many patients with DVs associated with elderly ages of onset, particularly in the presence of a family history

Fig. 5

Family history is a strong predictor for the identification of a deleterious or likely deleterious variant Stratifying cases by Goldman Score reveals its strong predictive value in identifying cases with a DV; however, deleterious or likely deleterious variants are found in clinically relevant proportions of cases with no (GS4) or a censored (GS4.5) family history

Fig. 6

Suggested decision making about use of dementia gene-panel testing. We found gene-panel diagnostics was most useful in AD and FTD syndromes where it was hard to predict the implicated single gene. Yield of clinically relevant mutations was high (> 10%), medium (5–10%) or low (< 5%) in groups stratified by age and family history. The decision to refer for gene-panel diagnostics is not solely driven by the chance of a clinically relevant result, and many clinicians would consider even a low yield (< 5%) justifies use of a gene-panel in many clinical scenarios. A decision should take into consideration the wishes of the patient and at-risk individuals. FTD subtype (behavioural variant, progressive non-fluent aphasia, semantic dementia, etc.) may also influence the approach to testing but this requires further study. Suspected prion disease patients are best referred for PRNP testing in the first instance, and if this is negative, reconsider as per AD syndrome. Dementia-motor syndromes had a generally low yield on dementia panel testing (< 5% all subgroups), recommendations have been made for the stepwise investigation of HD-like syndromes, which are often caused by expansion disorders not well ascertained by gene-panel diagnostics [5]