The impact of age on genetic testing decisions in amyotrophic lateral sclerosis

Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative syndrome. In up to
20%, a family history is observed. Although Mendelian disease gene variants are found in
apparently sporadic ALS, genetic testing is usually restricted to those with a family history or
younger patients with sporadic disease. With the advent of therapies targeting genetic ALS, it
is important that everyone treatable is identified. We therefore sought to determine the
probability of a clinically actionable ALS genetic test result by age of onset globally, but using
the UK as an exemplar.
Blood-derived DNA was sequenced for ALS genes, and the probability of a clinically
actionable genetic test result estimated. For a UK subset, age and sex-specific population
incidence rates were used to determine the number of such results missed by restricting testing
by age of onset according to UK’s National Genomic Test Directory criteria.
There were 6274 people with sporadic ALS, 1551 from the UK. The proportion with a
clinically actionable genetic test result ranged between 0.21 (95% CI 0.18-0.25) in the youngest
age group to 0.15 (95% CI 0.13-0.17) in the oldest age group for a full gene panel. For the UK,
the equivalent proportions were 0.23 (95% CI 0.13-0.33) in the youngest age group to 0.17
(95% CI 0.13-0.21) in the oldest age group. By limiting testing in those without a family history
to people with onset below 40 years, 115 of 117 (98% of all, 95% CI 0.96-1.01) clinically
actionable test results were missed.
There is a significant probability of a clinically actionable genetic test result in people with
apparently sporadic ALS at all ages. Although some countries limit testing by age, doing so
results in a significant number of missed pathogenic test results. Age of onset and family
history should not be a barrier to genetic testing in ALS.