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

Project MinE ALS Sequencing Consortium; Puja R Mehta; Alfredo Iacoangeli; Sarah Opie-Martin; Joke J F A van Vugt; Ahmad Al Khleifat; Andrea Bredin; Lynn Ossher; Peter M Andersen; Orla Hardiman; Arpan R Mehta; Pietro Fratta; Kevin Talbot; Ammar Al-Chalabi

doi:10.1093/brain/awac279

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

Project MinE ALS Sequencing Consortium, Puja R Mehta, Alfredo Iacoangeli, Sarah Opie-Martin, Joke J F A van Vugt, Ahmad Al Khleifat, Andrea Bredin, Lynn Ossher, Peter M Andersen, Orla Hardiman, Arpan R Mehta, Pietro Fratta, Kevin Talbot, Ammar Al-Chalabi

Research output: Contribution to journal › Article › peer-review

21 Citations (Scopus)

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. [Abstract copyright: © The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.]

Original language	English
Article number	awac279
Journal	Brain : a journal of neurology
Early online date	27 Sept 2022
DOIs	https://doi.org/10.1093/brain/awac279
Publication status	E-pub ahead of print - 27 Sept 2022

Keywords

motor neuron disease
age of onset
amyotrophic lateral sclerosis
genetic testing
genetic counselling

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10.1093/brain/awac279

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Project MinE ALS Sequencing Consortium, Mehta, P. R., Iacoangeli, A., Opie-Martin, S., van Vugt, J. J. F. A., Al Khleifat, A., Bredin, A., Ossher, L., Andersen, P. M., Hardiman, O., Mehta, A. R., Fratta, P., Talbot, K., & Al-Chalabi, A. (2022). The impact of age on genetic testing decisions in amyotrophic lateral sclerosis. Brain : a journal of neurology, Article awac279. Advance online publication. https://doi.org/10.1093/brain/awac279

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title = "The impact of age on genetic testing decisions in amyotrophic lateral sclerosis",

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. [Abstract copyright: {\textcopyright} The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.]",

keywords = "motor neuron disease, age of onset, amyotrophic lateral sclerosis, genetic testing, genetic counselling",

author = "{Project MinE ALS Sequencing Consortium} and Mehta, {Puja R} and Alfredo Iacoangeli and Sarah Opie-Martin and {van Vugt}, {Joke J F A} and {Al Khleifat}, Ahmad and Andrea Bredin and Lynn Ossher and Andersen, {Peter M} and Orla Hardiman and Mehta, {Arpan R} and Pietro Fratta and Kevin Talbot and Ammar Al-Chalabi",

year = "2022",

month = sep,

day = "27",

doi = "10.1093/brain/awac279",

language = "English",

journal = "Brain : a journal of neurology",

issn = "0006-8950",

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T1 - The impact of age on genetic testing decisions in amyotrophic lateral sclerosis

AU - Project MinE ALS Sequencing Consortium

AU - Mehta, Puja R

AU - Iacoangeli, Alfredo

AU - Opie-Martin, Sarah

AU - van Vugt, Joke J F A

AU - Al Khleifat, Ahmad

AU - Bredin, Andrea

AU - Ossher, Lynn

AU - Andersen, Peter M

AU - Hardiman, Orla

AU - Mehta, Arpan R

AU - Fratta, Pietro

AU - Talbot, Kevin

AU - Al-Chalabi, Ammar

PY - 2022/9/27

Y1 - 2022/9/27

N2 - 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. [Abstract copyright: © The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.]

AB - 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. [Abstract copyright: © The Author(s) 2022. Published by Oxford University Press on behalf of the Guarantors of Brain.]

KW - motor neuron disease

KW - age of onset

KW - amyotrophic lateral sclerosis

KW - genetic testing

KW - genetic counselling

U2 - 10.1093/brain/awac279

DO - 10.1093/brain/awac279

M3 - Article

C2 - 36162820

SN - 0006-8950

JO - Brain : a journal of neurology

JF - Brain : a journal of neurology

M1 - awac279

ER -

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

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Keywords

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