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Genetics and genomics
Research
Molecular diagnosis of inherited peripheral neuropathies by targeted next-generation sequencing: molecular spectrum delineation
  1. Juliette Bacquet1,
  2. Tanya Stojkovic2,
  3. Amandine Boyer1,
  4. Nathalie Martini1,
  5. Frédérique Audic3,
  6. Brigitte Chabrol3,
  7. Emmanuelle Salort-Campana4,5,
  8. Emilien Delmont4,
  9. Jean-Pierre Desvignes5,
  10. Annie Verschueren4,
  11. Shahram Attarian4,5,
  12. Annabelle Chaussenot6,
  13. Valérie Delague5,
  14. Nicolas Levy1,5,
  15. Nathalie Bonello-Palot1,5
  1. 1 Département de génétique médicale, Hôpital Timone enfants, Assistance Publique Hôpitaux de Marseille, Marseille, France
  2. 2 Centre de référence des maladies neuromusculaires, Hôpital Pitié-Salpétrière, Assistance-Publique Hôpitaux de Paris, Paris, France
  3. 3 Centre de référence des maladies neuromusculaires, Hôpital Timone enfants, Assistance Publique Hôpitaux de Marseille, Marseille, France
  4. 4 Centre de référence des maladies neuromusculaires, Hôpital Timone Adultes, Assistance Publique Hôpitaux de Marseille, Marseille, France
  5. 5 INSERM, MMG, UMR 1251, Aix Marseille Univ, Marseille, France
  6. 6 Département de génétique médicale, Hôpital Archet 2, CHU de Nice, Nice, France
  1. Correspondence to Dr Juliette Bacquet; juliette.bacquet{at}ap-hm.fr

Abstract

Purpose Inherited peripheral neuropathies (IPN) represent a large heterogenous group of hereditary diseases with more than 100 causative genes reported to date. In this context, targeted next-generation sequencing (NGS) offers the opportunity to screen all these genes with high efficiency in order to unravel the genetic basis of the disease. Here, we compare the diagnostic yield of targeted NGS with our previous gene by gene Sanger sequencing strategy. We also describe several novel likely pathogenic variants.

Design and participants We have completed the targeted NGS of 81 IPN genes in a cohort of 123 unrelated patients affected with diverse forms of IPNs, mostly Charcot-Marie-Tooth disease (CMT): 23% CMT1, 52% CMT2, 9% distal hereditary motor neuropathy, 7% hereditary sensory and autonomic neuropathy and 6.5% intermediate CMT.

Results We have solved the molecular diagnosis in 49 of 123 patients (~40%). Among the identified variants, 26 variants were already reported in the literature. In our cohort, the most frequently mutated genes are respectively: MFN2, SH3TC2, GDAP1, NEFL, GAN, KIF5A and AARS. Panel-based NGS was more efficient in familial cases than in sporadic cases (diagnostic yield 49%vs19%, respectively). NGS-based search for copy number variations, allowed the identification of three duplications in three patients and raised the diagnostic yield to 41%. This yield is two times higher than the one obtained previously by gene Sanger sequencing screening. The impact of panel-based NGS screening is particularly important for demyelinating CMT (CMT1) subtypes, for which the success rate reached 87% (36% only for axonal CMT2).

Conclusion NGS allowed to identify causal mutations in a shorter and cost-effective time. Actually, targeted NGS is a well-suited strategy for efficient molecular diagnosis of IPNs. However, NGS leads to the identification of numerous variants of unknown significance, which interpretation requires interdisciplinary collaborations between molecular geneticists, clinicians and (neuro)pathologists.

  • next generation sequencing
  • copy number variation
  • inherited peripheral neuropathies
  • mutation

This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.

https://doi.org/10.1136/bmjopen-2018-021632

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    Footnotes

    • Contributors JB, NB-P, VD and NL contributed to the design of the study. NB-P contributed to the supervision and mentorship. JB, AB, J-PD and NM participated in data analysis and interpretation. JB, TS and NB-P contributed to manuscript drafting. TS, FA, BC, ES-C, ED, AV, SA, AC and NL contributed to the collection of clinical data during consultations. All authors participated in critical revisions of the manuscript and can take responsibility for its integrity and the accuracy of the data analysis.

    • 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.

    • Patient consent obtained.

    • Ethics approval Aix-Marseille University Ethics Comittee.

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

    • Data sharing statement The data are not available freely. Enquiries and requests for further information should be made to corresponding author.