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Genetic diagnosis and detection rates using C9orf72 repeat expansion and a multi-gene panel in amyotrophic lateral sclerosis

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Abstract

Amyotrophic lateral sclerosis (ALS) is a progressive neurodegenerative disorder. It is mostly sporadic, with the C9orf72 repeat expansion being the most common genetic cause. While the prevalence of C9orf72-ALS in patients from different populations has been studied, data regarding the yield of C9orf72 compared to an ALS gene panel testing is limited.

We aimed to explore the application of C9orf72 versus a gene panel in the general Israeli population. A total of 140 ALS patients attended our Neurogenetics Clinic throughout 2018–2023. Disease onset was between ages 60 and 69 years for most patients (34%); however, a quarter had an early-onset disease (< 50 years). Overall, 119 patients (85%) were genetically evaluated: 116 (97%) were tested for the C9orf72 repeat expansion and 64 (54%) underwent gene panel testing. The C9orf72 repeat expansion had a prevalence of 21% among Ashkenazi Jewish patients compared to 5.7% in non-Ashkenazi patients, while the gene panel had a higher yield in non-Ashkenazi patients with 14% disease-causing variants compared to 5.7% in Ashkenazi Jews. Among early-onset ALS patients, panel testing was positive in 12% compared to 2.9% for C9orf72.

We suggest a testing strategy for the Israeli ALS patients: C9orf72 should be the first-tier test in Ashkenazi Jewish patients, while a gene panel should be considered as the first step in non-Ashkenazi and early-onset patients. Tiered testing has important implications for patient management, including prognosis, ongoing clinical trials, and prevention in future generations. Similar studies should be implemented worldwide to uncover the diverse ALS genetic architecture and facilitate tailored care.

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Data availability

Data related to the study are available from the corresponding authors upon reasonable request.

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Acknowledgements

We thank the patients and their families, and acknowledge the Molecular Genetics Laboratory and the Genomics Center staff at the Tel Aviv Sourasky Medical Center for performing the genetic workup.

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None.

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Author notes

  1. Dalit Barel, Daphna Marom, Penina Ponger, Alina Kurolap are Equal contribution.

  2. Vivian Drory, Hagit Baris Feldman are Equal contribution.

Authors and Affiliations

  1. The Genetics Institute and Genomics Center, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

    Dalit Barel, Daphna Marom, Penina Ponger, Alina Kurolap, Anat Bar-Shira, Idit Kaplan-Ber, Adi Mory, Yuval Yaron & Hagit Baris Feldman

  2. Department of Neurology, Tel Aviv Sourasky Medical Center, Tel Aviv, Israel

    Penina Ponger, Beatrice Abramovich & Vivian Drory

  3. Faculty of Medical and Health Sciences, School of Medicine, Tel Aviv University, Tel Aviv, Israel

    Daphna Marom, Yuval Yaron, Vivian Drory & Hagit Baris Feldman

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  1. Dalit Barel
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Correspondence to Dalit Barel or Hagit Baris Feldman.

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The authors declare no conflicts of interest.

Ethical approval

Genetic testing was performed as a clinical service under standard clinical consent forms. The study was approved by the Tel Aviv Sourasky Medical Center Institutional Helsinki Committee (#0586–20-TLV), which grants a waiver of informed consent for retrospective study of patient medical records.

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Barel, D., Marom, D., Ponger, P. et al. Genetic diagnosis and detection rates using C9orf72 repeat expansion and a multi-gene panel in amyotrophic lateral sclerosis. J Neurol (2024). https://doi.org/10.1007/s00415-024-12368-3

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  • DOI: https://doi.org/10.1007/s00415-024-12368-3

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