Article Text

Download PDFPDF
Original research
Effect of familial clustering in the genetic screening of 235 French ALS families
  1. Philippe Corcia1,2,
  2. William Camu3,
  3. Celine Brulard2,
  4. Sylviane Marouillat2,
  5. Philippe Couratier4,5,
  6. Jean-Philippe Camdessanché6,
  7. Pascal Cintas7,
  8. Annie Verschueren8,
  9. Marie-Helene Soriani9,
  10. Claude Desnuelle10,
  11. Marie-Céline Fleury11,
  12. Nathalie Guy12,
  13. Julien Cassereau13,
  14. Fausto Viader14,
  15. Sophie Pittion-Vouyovitch15,
  16. Veronique Danel16,
  17. Ivan Kolev17,
  18. Gwendal Le Masson18,
  19. Stephane Beltran19,
  20. Francois Salachas20,
  21. Emilien Bernard21,
  22. Pierre-François Pradat22,23,
  23. Hélène Blasco24,25,
  24. Débora Lanznaster2,
  25. Rudolph Hergesheimer2,
  26. Frederic Laumonnier2,
  27. Christian R Andres24,
  28. Vincent Meininger25,
  29. Patrick Vourc'h24
  1. 1 ALS Centre, Department of Neurology, CHU Tours, Tours, Centre, France
  2. 2 UMR 1253 Imaging and Brain, Tours, Centre-Val de Loire, France
  3. 3 Montpellier 2 University, Montpellier, Languedoc-Roussillon, France
  4. 4 ALS Center, Departement of neurology, CHU Limoges, Limoges, Limousin, France
  5. 5 UMR-S 1094 NET, Limoges, France
  6. 6 Neurology, Saint-Etienne University Hospital Bellevue Site, Saint-Etienne, Rhône-Alpes, France
  7. 7 Neurology, CHU Toulouse, Toulouse, Midi-Pyrénées, France
  8. 8 Centre de référence des maladies neuromusculaires et de la SLA, Marseille Public University Hospital System, Marseille, Provence-Alpes-Côte d'Azu, France
  9. 9 CHU Nice, Nice, Provence-Alpes-Côte d'Azu, France
  10. 10 Centre de reference des maladies neuromusculaires SLA, Neurosciences department, CHU Nice, Nice, Provence-Alpes-Côte d'Azu, France
  11. 11 Neurology, CHU Strasbourg, Strasbourg, Alsace, France
  12. 12 CHU Clermont-Ferrand, Clermont-Ferrand, France
  13. 13 Neurology, CHU Angers, Angers, Pays de la Loire, France
  14. 14 U1077, INSERM, Paris, Caen, France
  15. 15 Neurology, Hopital Central, Nancy, France
  16. 16 Medical Pharmacology, Lille University Hospital Center, Lille, Hauts-de-France, France
  17. 17 Hospital Centre Saint Brieuc, Saint Brieuc, Bretagne, France
  18. 18 Neurology, Centre Hospitalier Universitaire de Bordeaux Groupe Hospitalier Pellegrin, Bordeaux, Aquitaine, France
  19. 19 ALS Center, Francois-Rabelais University, Tours, Centre-Val de Loire, France
  20. 20 ALS Center, Neurology, Hopital Universitaire Pitie Salpetriere, Paris, Île-de-France, France
  21. 21 University Hospital Centre Lyon, Lyon, Auvergne-Rhône-Alpes, France
  22. 22 Fédération de Neurologie, Centre Référent SLA, Hopital Universitaire Pitie Salpetriere, Paris, Île-de-France, France
  23. 23 CNRS, INSERM, Laboratoire d’Imagerie Biomédicale (LIB), Université Pierre et Marie Curie Faculté de Médecine, Paris, Île-de-France, France
  24. 24 Biochemistry and Molecular Biology Department, Université Francois-Rabelais de Tours, Tours, Centre-Val de Loire, France
  25. 25 Neurogenetics and Neurometabolomics, Imagerie et cerveau, Tours, France
  1. Correspondence to Professor Philippe Corcia, ALS Centre, Department of Neurology, CHU Tours, Tours, Centre, France; corcia{at}med.univ-tours.fr

Abstract

Objectives To determine whether the familial clustering of amyotrophic lateral sclerosis (ALS) cases and the phenotype of the disease may help identify the pathogenic genes involved.

Methods We conducted a targeted next-generation sequencing analysis on 235 French familial ALS (FALS), unrelated probands to identify mutations in 30 genes linked to the disease. The genealogy, that is, number of cases and generations with ALS, gender, age, site of onset and the duration of the disease were analysed.

Results Regarding the number of generations, 49 pedigrees had only one affected generation, 152 had two affected generations and 34 had at least three affected generations. Among the 149 pedigrees (63.4%) for which a deleterious variant was found, an abnormal G4C2 expansion in C9orf72 was found in 98 cases as well as SOD1, TARBP or FUS mutations in 30, 9 and 7 cases, respectively. Considering pedigrees from the number of generations, abnormal G4C2 expansion in C9orf72 was more frequent in pedigrees with pairs of affected ALS cases, which represented 65.2% of our cohort. SOD1 mutation involved all types of pedigrees. No TARDBP nor FUS mutation was present in monogenerational pedigrees. TARDBP mutation predominated in bigenerational pedigrees with at least three cases and FUS mutation in multigenerational pedigrees with more than seven cases, on average, and with an age of onset younger than 45 years.

Conclusion Our results suggest that familial clustering, phenotypes and genotypes are interconnected in FALS, and thus it might be possible to target the genetic screening from the familial architecture and the phenotype of ALS cases.

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information. All data are deidentified and available at the Biochemistry and Molecular Biology Department of the CHU of Tours.

Statistics from Altmetric.com

Data availability statement

All data relevant to the study are included in the article or uploaded as supplementary information. All data are deidentified and available at the Biochemistry and Molecular Biology Department of the CHU of Tours.

View Full Text

Footnotes

  • Contributors P Corcia, WC, HB, FL and PV conceived the study, had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the analysis. P Corcia, WC, P Couratier, JPC, P Cintas, AV, MHS, CD, MCF, NG, JC, FV, SP, VDB, YK, GLM, FS, EB, PFP and VM helped with the implementation. PV, CB, RH, DL, SM and CA performed the genetic analysis. HB, P Corcia and WC performed the statistical analysis. All authors contributed to the refinement of the study protocol and approved the final manuscript.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Not commissioned; externally peer reviewed.

  • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.

Request Permissions

If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.