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Identification of novel pathogenic copy number variations in Charcot-Marie-Tooth disease


Charcot-Marie-Tooth disease (CMT) is a hereditary sensory-motor neuropathy characterized by a strong clinical and genetic heterogeneity. Over the past few years, with the occurrence of whole-exome sequencing (WES) or whole-genome sequencing (WGS), the molecular diagnosis rate has been improved by allowing the screening of more than 80 genes at one time. In CMT, except the recurrent PMP22 duplication accounting for about 60% of pathogenic variations, pathogenic copy number variations (CNVs) are rarely reported and only a few studies screening specifically CNVs have been performed. The aim of the present study was to screen for CNVs in the most prevalent genes associated with CMT in a cohort of 200 patients negative for the PMP22 duplication. CNVs were screened using the Exome Depth software on next generation sequencing (NGS) data obtained by targeted capture and sequencing of a panel of 81 CMT associated genes. Deleterious CNVs were identified in four patients (2%), in four genes: GDAP1, LRSAM1, GAN, and FGD4. All CNVs were confirmed by high-resolution oligonucleotide array Comparative Genomic Hybridization (aCGH) and/or quantitative PCR. By identifying four new CNVs in four different genes, we demonstrate that, although they are rare mutational events in CMT, CNVs might contribute significantly to mutational spectrum of Charcot-Marie-Tooth disease and should be searched in routine NGS diagnosis. This strategy increases the molecular diagnosis rate of patients with neuropathy.

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  1. 1.

    Skre H. Genetic and clinical aspects of Charcot-Marie-Tooth’s disease. Clin Genet. 1974;6:98–118.

    PubMed  CAS  Google Scholar 

  2. 2.

    Braathen GJ. Genetic epidemiology of Charcot-Marie-Tooth disease. Acta Neurol Scand Suppl. 2012;126:iv–22.

    Google Scholar 

  3. 3.

    Dyck P, Chance P, Lebo R, Carney A. Hereditary motor and sensory neuropathies. In: Dyck PJ, Griffiri JW, Low PA, Podulso JP, editors. Peripheral neuropathy 3rd ed. Philadelphia: WBSaunders Co; 1993. p. 1094–136.

  4. 4.

    Timmerman V, Strickland AV, Züchner S. Genetics of Charcot-Marie-Tooth (CMT) disease within the frame of the Human Genome Project success. Genes. 2014;5:13–32.

    PubMed  PubMed Central  CAS  Google Scholar 

  5. 5.

    Gonzaga-Jauregui C, Harel T, Gambin T, Kousi M, Griffin LB, Francescatto L, et al. Exome sequence analysis suggests that genetic burden contributes to phenotypic variability and complex neuropathy. Cell Rep. 2015;12:1169–83.

    PubMed  PubMed Central  CAS  Google Scholar 

  6. 6.

    Murphy SM, Laura M, Fawcett K, Pandraud A, Liu Y-T, Davidson GL, et al. Charcot-Marie-Tooth disease: frequency of genetic subtypes and guidelines for genetic testing. J Neurol Neurosurg Psychiatry. 2012;83:706–10.

    PubMed  PubMed Central  Google Scholar 

  7. 7.

    Saporta ASD, Sottile SL, Miller LJ, Feely SME, Siskind CE, Shy ME. Charcot-Marie-Tooth disease subtypes and genetic testing strategies. Ann Neurol. 2011;69:22–33.

    PubMed  PubMed Central  Google Scholar 

  8. 8.

    Lupski JR, Garcia CA. Charcot‐Marie‐Tooth peripheral neuropathies and related disorders. In: Scriver CR, Beaudet AL, Sly WS, Valle D, editors. The metabolic and molecular basis of inherited diseases. New York: McGraw‐Hill; 2001. p. 5759–88.

  9. 9.

    Bacquet J, Stojkovic T, Boyer A, Martini N, Audic F, Chabrol B, et al. Molecular diagnosis of inherited peripheral neuropathies by targeted next-generation sequencing: molecular spectrum delineation. BMJ Open. 2018;8:e021632.

    PubMed  PubMed Central  Google Scholar 

  10. 10.

    Hoebeke C, Bonello-Palot N, Audic F, Boulay C, Tufod D, Attarian S, et al. Retrospective study of 75 children with peripheral inherited neuropathy: genotype–phenotype correlations. Arch Pediatr Organe Soc Francaise Pediatr. 2018;25:452–8.

    CAS  Google Scholar 

  11. 11.

    Robinson JT, Thorvaldsdóttir H, Winckler W, Guttman M, Lander ES, Getz G, et al. Integrative genomics viewer. Nat Biotechnol. 2011;29:24–6.

    PubMed  PubMed Central  CAS  Google Scholar 

  12. 12.

    Lacoste C, Fabre A, Pécheux C, Lévy N, Krahn M, Malzac P. et al. Next-generation DNA sequencing in clinical diagnostics. Arch Pediatr Organe Off Soc Francaise Pediatr. 2017;24:373–83.

    CAS  Google Scholar 

  13. 13.

    Plagnol V, Curtis J, Epstein M, Mok KY, Stebbings E, Grigoriadou S, et al. A robust model for read count data in exome sequencing experiments and implications for copy number variant calling. Bioinform Oxf Engl. 2012;28:2747–54.

    CAS  Google Scholar 

  14. 14.

    Ellingford JM, Campbell C, Barton S, Bhaskar S, Gupta S, Taylor RL, et al. Validation of copy number variation analysis for next-generation sequencing diagnostics. Eur J Hum Genet. 2017;25:719–24.

    PubMed  PubMed Central  CAS  Google Scholar 

  15. 15.

    Aarskog NK, Vedeler CA. Real-time quantitative polymerase chain reaction. A new method that detects both the peripheral myelin protein 22 duplication in Charcot-Marie-Tooth type 1A disease and the peripheral myelin protein 22 deletion in hereditary neuropathy with liability to pressure palsies. Hum Genet. 2000;107:494–8.

    PubMed  CAS  Google Scholar 

  16. 16.

    Landrum MJ, Lee JM, Benson M, Brown GR, Chao C, Chitipiralla S, et al. ClinVar: improving access to variant interpretations and supporting evidence. Nucleic Acids Res. 2018;46:D1062–7.

    PubMed  CAS  Google Scholar 

  17. 17.

    MacDonald JR, Ziman R, Yuen RKC, Feuk L, Scherer SW. The database of genomic variants: a curated collection of structural variation in the human genome. Nucleic Acids Res. 2014;42:D986–92.

    PubMed  CAS  Google Scholar 

  18. 18.

    Firth HV, Richards SM, Bevan AP, Clayton S, Corpas M, Rajan D, et al. DECIPHER: database of chromosomal imbalance and phenotype in humans using ensemble resources. Am J Hum Genet. 2009;84:524–33.

    PubMed  PubMed Central  CAS  Google Scholar 

  19. 19.

    Bird T. Charcot-Marie-Tooth (CMT) hereditary neuropathy overview. In: Adam MP, Ardinger HH, Pagon RA, et al. editors. GeneReviews®. Seattle (WA): University of Washington, Seattle; 1998. Disponible sur:

  20. 20.

    Timmerman V, Nelis E, Van Hul W, Nieuwenhuijsen BW, Chen KL, Wang S, et al. The peripheral myelin protein gene PMP-22 is contained within the Charcot-Marie-Tooth disease type 1A duplication. Nat Genet. 1992;1:171–5.

    PubMed  CAS  Google Scholar 

  21. 21.

    Lupski JR. An inherited DNA rearrangement and gene dosage effect are responsible for the most common autosomal dominant peripheral neuropathy: Charcot-Marie-Tooth disease type 1A. Clin Res. 1992;40:645–52.

    PubMed  CAS  Google Scholar 

  22. 22.

    Huang J, Wu X, Montenegro G, Price J, Wang G, Vance JM, et al. Copy number variations are a rare cause of non-CMT1A Charcot-Marie-Tooth disease. J Neurol. 2010;257:735–41.

    PubMed  Google Scholar 

  23. 23.

    Gonzaga-Jauregui C, Zhang F, Towne CF, Batish SD, Lupski JR. GJB1/Connexin 32 whole gene deletions in patients with X-linked Charcot-Marie-Tooth disease. Neurogenetics. 2010;11:465–70.

    PubMed  PubMed Central  CAS  Google Scholar 

  24. 24.

    Speevak MD, Farrell SA. Charcot-Marie-Tooth 1B caused by expansion of a familial myelin protein zero (MPZ) gene duplication. Eur J Med Genet. 2013;56:566–9.

    PubMed  Google Scholar 

  25. 25.

    Okamoto Y, Goksungur MT, Pehlivan D, Beck CR, Gonzaga-Jauregui C, Muzny DM, et al. Exonic duplication CNV of NDRG1 associated with autosomal-recessive HMSN-Lom/CMT4D. Genet Med. 2014;16:386–94.

    PubMed  CAS  Google Scholar 

  26. 26.

    Høyer H, Braathen GJ, Eek AK, Nordang GBN, Skjelbred CF, Russell MB. Copy number variations in a population-based study of Charcot-Marie-Tooth disease. Biomed Res Int. 2015;2015:960404.

    PubMed  PubMed Central  Google Scholar 

  27. 27.

    Pehlivan D, Beck CR, Okamoto Y, Harel T, Akdemir ZHC, Jhangiani SN, et al. The role of combined SNV and CNV burden in patients with distal symmetric polyneuropathy. Genet Med. 2016;18:443–51.

    PubMed  Google Scholar 

  28. 28.

    Dohrn MF, Glöckle N, Mulahasanovic L, Heller C, Mohr J, Bauer C, et al. Frequent genes in rare diseases: panel-based next generation sequencing to disclose causal mutations in hereditary neuropathies. J Neurochem. 2017;143:507–22.

    PubMed  CAS  Google Scholar 

  29. 29.

    Salpietro V, Manole A, Efthymiou S, Houlden H. A review of copy number variants in inherited neuropathies. Curr Genomics. 2018;19:412–9.

    PubMed  PubMed Central  CAS  Google Scholar 

  30. 30.

    Harel T, Lupski JR. Genomic disorders 20 years on-mechanisms for clinical manifestations. Clin Genet. 2018;93:439–49.

    PubMed  CAS  Google Scholar 

  31. 31.

    Bomont P, Cavalier L, Blondeau F, Ben Hamida C, Belal S, Tazir M, et al. The gene encoding gigaxonin, a new member of the cytoskeletal BTB/kelch repeat family, is mutated in giant axonal neuropathy. Nat Genet. 2000;26:370–4.

    PubMed  CAS  Google Scholar 

  32. 32.

    Aharoni S, Barwick KES, Straussberg R, Harlalka GV, Nevo Y, Chioza BA, et al. Novel homozygous missense mutation in GAN associated with Charcot-Marie-Tooth disease type 2 in a large consanguineous family from Israel. BMC Med Genet. 2016;17:82.

    PubMed  PubMed Central  Google Scholar 

  33. 33.

    Buysse K, Vergult S, Mussche S, Ceuterick-de Groote C, Speleman F, Menten B, et al. Giant axonal neuropathy caused by compound heterozygosity for a maternally inherited microdeletion and a paternal mutation within the GAN gene. Am J Med Genet A. 2010;152A:2802–4.

    PubMed  CAS  Google Scholar 

  34. 34.

    Baxter RV, Ben Othmane K, Rochelle JM, Stajich JE, Hulette C, Dew-Knight S, et al. Ganglioside-induced differentiation-associated protein-1 is mutant in Charcot-Marie-Tooth disease type 4A/8q21. Nat Genet. 2002;30:21–2.

    PubMed  CAS  Google Scholar 

  35. 35.

    Cuesta A, Pedrola L, Sevilla T, García-Planells J, Chumillas MJ, Mayordomo F, et al. The gene encoding ganglioside-induced differentiation-associated protein 1 is mutated in axonal Charcot-Marie-Tooth type 4A disease. Nat Genet. 2002;30:22–5.

    PubMed  CAS  Google Scholar 

  36. 36.

    Cassereau J, Chevrollier A, Gueguen N, Malinge M-C, Letournel F, Nicolas G, et al. Mitochondrial complex I deficiency in GDAP1-related autosomal dominant Charcot-Marie-Tooth disease (CMT2K). Neurogenetics. 2009;10:145–50.

    PubMed  CAS  Google Scholar 

  37. 37.

    Zimoń M, Battaloğlu E, Parman Y, Erdem S, Baets J, De Vriendt E, et al. Unraveling the genetic landscape of autosomal recessive Charcot-Marie-Tooth neuropathies using a homozygosity mapping approach. Neurogenetics. 2015;16:33–42.

    PubMed  Google Scholar 

  38. 38.

    Niyazov D, Africk D. Mitochondrial dysfunction in a patient with 8q21.11 deletion and Charcot-Marie-Tooth disease type 2K due to GDAP1 haploinsufficiency. Mol Syndromol. 2015;6:204–6.

    PubMed  PubMed Central  CAS  Google Scholar 

  39. 39.

    Guernsey DL, Jiang H, Bedard K, Evans SC, Ferguson M, Matsuoka M, et al. Mutation in the gene encoding ubiquitin ligase LRSAM1 in patients with Charcot-Marie-Tooth disease. PLoS Genet. 2010;6:e1001081

    PubMed  PubMed Central  Google Scholar 

  40. 40.

    Weterman MAJ, Sorrentino V, Kasher PR, Jakobs ME, van Engelen BGM, Fluiter K, et al. A frameshift mutation in LRSAM1 is responsible for a dominant hereditary polyneuropathy. Hum Mol Genet. 2012;21:358–70.

    PubMed  CAS  Google Scholar 

  41. 41.

    Peeters K, Palaima P, Pelayo-Negro AL, García A, Gallardo E, García-Barredo R, et al. Charcot-Marie-Tooth disease type 2G redefined by a novel mutation in LRSAM1. Ann Neurol. 2016;80:823–33.

    PubMed  CAS  Google Scholar 

  42. 42.

    Hakonen JE, Sorrentino V, Avagliano Trezza R, de Wissel MB, van den Berg M, Bleijlevens B, et al. LRSAM1-mediated ubiquitylation is disrupted in axonal Charcot-Marie-Tooth disease 2P. Hum Mol Genet. 2017;26:2034–41.

    PubMed  CAS  Google Scholar 

  43. 43.

    Peretti A, Perie M, Vincent D, Bouhour F, Dieterich K, Mallaret M, et al. LRSAM1 variants and founder effect in French families with ataxic form of Charcot-Marie-Tooth type 2. Eur J Hum Genet. 2019;17:1.

  44. 44.

    Delague V, Jacquier A, Hamadouche T, Poitelon Y, Baudot C, Boccaccio I, et al. Mutations in FGD4 encoding the Rho GDP/GTP exchange factor FRABIN cause autosomal recessive Charcot-Marie-Tooth type 4H. Am J Hum Genet. 2007;81:1–16.

    PubMed  PubMed Central  CAS  Google Scholar 

  45. 45.

    Richards S, Aziz N, Bale S, Bick D, Das S, Gastier-Foster J, et al. Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. Genet Med. 2015;17:405–24.

    PubMed  PubMed Central  Google Scholar 

  46. 46.

    Riggs ER, Andersen EF, Cherry AM, Kantarci S, Kearney H, Patel A, et al. Technical standards for the interpretation and reporting of constitutional copy-number variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics (ACMG) and the Clinical Genome Resource (ClinGen). Genet Med Off J Am Coll Med Genet. 2019;6:1–13.

  47. 47.

    Brewer MH, Chaudhry R, Qi J, Kidambi A, Drew AP, Menezes MP, et al. Whole genome sequencing identifies a 78 kb insertion from chromosome 8 as the cause of Charcot-Marie-Tooth neuropathy CMTX3. PLoS Genet. 2016;12:e1006177.

    PubMed  PubMed Central  Google Scholar 

  48. 48.

    Drew AP, Cutrupi AN, Brewer MH, Nicholson GA, Kennerson ML. A 1.35 Mb DNA fragment is inserted into the DHMN1 locus on chromosome 7q34–q36.2. Hum Genet. 2016;135:1269–78.

    PubMed  CAS  Google Scholar 

  49. 49.

    Cutrupi AN, Brewer MH, Nicholson GA, Kennerson ML. Structural variations causing inherited peripheral neuropathies: a paradigm for understanding genomic organization, chromatin interactions, and gene dysregulation. Mol Genet Genom Med. 2018;6:422–33.

    CAS  Google Scholar 

  50. 50.

    Goodwin S, McPherson JD, McCombie WR. Coming of age: ten years of next-generation sequencing technologies. Nat Rev Genet. 2016;17:333–51.

    PubMed  CAS  Google Scholar 

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We sincerely thank Caroline Lacoste, Christophe Pécheux, Karine Bertaux, Cécile Mouradian, Pierre Ceccaldi for their contribution to this work. We also wish to thank the patients, families and health professionals whose participation made possible this research.

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Correspondence to N. Bonello-Palot.

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Mortreux, J., Bacquet, J., Boyer, A. et al. Identification of novel pathogenic copy number variations in Charcot-Marie-Tooth disease. J Hum Genet 65, 313–323 (2020).

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