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Profilin1 E117G is a moderate risk factor for amyotrophic lateral sclerosis
  1. Pietro Fratta1,2,
  2. James Charnock2,
  3. Toby Collins2,
  4. Anny Devoy2,
  5. Robin Howard1,3,
  6. Andrea Malaspina4,
  7. Richard Orrell1,5,
  8. Katie Sidle1,3,
  9. Jan Clarke1,3,
  10. Maryam Shoai5,
  11. Ching-hua Lu4,6,
  12. John Hardy5,
  13. Vincent Plagnol7,
  14. Elizabeth M C Fisher1,2
  1. 1MRC Centre for Neuromuscular Diseases, UCL Institute of Neurology, London, UK
  2. 2Department of Neurodegenerative Diseases, UCL Institute of Neurology, London, UK
  3. 3National Hospital for Neurology and Neurosurgery, London, UK
  4. 4Centre for Neuroscience & Trauma, Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK
  5. 5Department of Molecular Neuroscience, UCL Institute of Neurology, London, UK
  6. 6Sobell Department of Motor Neuroscience and Movement Disorders, UCL Institute of Neurology, London, UK
  7. 7UCL Genetics Institute, University College London, London, UK
  1. Correspondence to Dr Pietro Fratta, Department of Neurodegenerative Diseases, UCL Institute of Neurology, Queen Square, London WC1N 3BG, UK; p.fratta{at}prion.ucl.ac.uk

Abstract

Background Amyotrophic lateral sclerosis (ALS) and frontotemporal dementia (FTD) are progressive neurodegenerative disorders that share significant clinical, pathological and genetic overlap and are considered to represent different ends of a common disease spectrum. Mutations in Profilin1 have recently been described as a rare cause of familial ALS. The PFN1 E117G missense variant has been described in familial and sporadic cases, and also found in controls, casting doubt on its pathogenicity. Interpretation of such variants represents a significant clinical-genetics challenge.

Objective and results Here, we combine a screen of a new cohort of 383 ALS patients with multiple-sequence datasets to refine estimates of the ALS and FTD risk associated with PFN1 E117G. Together, our cohorts add up to 5118 ALS and FTD cases and 13 089 controls. We estimate a frequency of E117G of 0.11% in controls and 0.25% in cases. Estimated odds after population stratification is 2.44 (95% CI 1.048 to ∞, Mantel-Haenszel test p=0.036).

Conclusions Our results show an association between E117G and ALS, with a moderate effect size.

  • ALS
  • Neurogenetics

This is an Open Access article distributed in accordance with the terms of the Creative Commons Attribution (CC BY 3.0) license, which permits others to distribute, remix, adapt and build upon this work, for commercial use, provided the original work is properly cited. See: http://creativecommons.org/licenses/by/3.0/

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