The impact of age on genetic testing decisions in amyotrophic lateral sclerosis - PubMed (original) (raw)

. 2022 Dec 19;145(12):4440-4447.

doi: 10.1093/brain/awac279.

Alfredo Iacoangeli 2 3 4, Sarah Opie-Martin 2, Joke J F A van Vugt 5, Ahmad Al Khleifat 2, Andrea Bredin 2, Lynn Ossher 6, Peter M Andersen 7, Orla Hardiman 8, Arpan R Mehta 9 10, Pietro Fratta 1, Kevin Talbot 6; Project MinE ALS Sequencing Consortium; Ammar Al-Chalabi 2 4 11

Collaborators, Affiliations

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

Puja R Mehta et al. Brain. 2022.

Abstract

Amyotrophic lateral sclerosis (ALS) is a heterogeneous neurodegenerative syndrome. In up to 20% of cases, 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% confidence interval (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 96%-101%) 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.

Keywords: age of onset; amyotrophic lateral sclerosis; genetic counselling; genetic testing; motor neuron disease.

© The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.

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Figures

Figure 1

Figure 1

Distribution of identified variants in the Global Project MinE cohort and their classification by ACMG criteria.

Figure 2

Figure 2

Probability of a person with ALS having a clinically actionable genetic test result given their age of onset. (A) Global Project MinE cohort. (B) UK cohort. Error bars denote 95% CI.

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