Modelling Population Genetic Screening in Rare Neurodegenerative Diseases

Importance: Genomic sequencing enables the rapid identification of a breadth of genetic variants. For clinical purposes, sequencing for small genetic variations is considered a solved problem, while challenges remain for structural variants, given the lower sensitivity and specificity. Interest has recently risen among governing bodies in developing protocols for population-wide genetic screening. However, usefulness is constrained when the probability of being affected by a rare disease remains low, despite a positive genetic test. This is a common scenario in neurodegenerative disorders. The problem is recognised among statisticians and statistical geneticists but is less well-understood by clinicians and researchers who will act on these results, and by the general public who might access screening services directly without the appropriate support for interpretation.

Observations: We explore the probability of subsequent disease following genetic screening of several variants, both single nucleotide variants (SNVs) and larger repeat expansions, for two neurological conditions, Huntington’s disease (HD) and amyotrophic lateral sclerosis (ALS), comparing these results with screening for phenylketonuria, which is well-established. The risk following a positive screening test was 0.5% for C9orf72 in ALS and 0.4% for HTT in HD when testing repeat expansions, for which the test had sub-optimal performance (sensitivity = 99% and specificity = 90%), and 12.7% for phenylketonuria and 10.9% for ALS SOD1 when testing pathogenic SNVs (sensitivity = 99.96% and specificity = 99.95%). Subsequent screening confirmation via PCR for C9orf72 led to a 2% risk of developing ALS as a result of the reduced penetrance (44%).

Conclusions and Relevance: We show that risk following a positive screening test result can be strikingly low for rare neurological diseases, even for fully penetrant variants such as HTT, if the test has sub-optimal performance. Accordingly, to maximise the utility of screening, it is vital to prioritise protocols with very high sensitivity and specificity, and a careful selection of markers for screening, giving regard to clinical interpretability, actionability, high penetrance, and secondary testing to confirm positive findings.