{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T02:32:57Z","timestamp":1790649177080,"version":"4.1.0"},"reference-count":25,"publisher":"MDPI AG","issue":"2","license":[{"start":{"date-parts":[[2022,2,3]],"date-time":"2022-02-03T00:00:00Z","timestamp":1643846400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JPM"],"abstract":"<jats:p>Next-generation sequencing (NGS) allows the detection of plentiful mutations increasing the rate of patients getting a positive diagnosis. However, while single-nucleotide variants (SNVs) or small indels can be easily detected, structural variations (SVs) such as copy number variants (CNVs) are often not researched. In Charcot\u2013Marie\u2013Tooth disease (CMT), the most common hereditary peripheral neuropathy, the PMP22-duplication was the first variation detected. Since then, more than 90 other genes have been associated with CMT, with point mutations or small indels mostly described. Herein, we present a personalized approach we performed to obtain a positive diagnosis of a patient suffering from demyelinating CMT. His NGS data were aligned to the human reference sequence but also studied using the CovCopCan software, designed to detect large CNVs. This approach allowed the detection of only one mutation in SH3TC2, the frequent p.Arg954*, while SH3TC2 is known to be responsible for autosomal recessive demyelinating CMT forms. Interestingly, by modifying the standard CovCopCan use, we detected the second mutation of this patient corresponding to a 922 bp deletion in SH3TC2 (Chr5:148,390,609-Chr5:148,389,687), including only one exon (exon 14). This highlights that SVs, different from PMP22 duplication, can be responsible for peripheral neuropathy and should be searched systematically. This approach could also be employed to improve the diagnosis of all inherited diseases.<\/jats:p>","DOI":"10.3390\/jpm12020212","type":"journal-article","created":{"date-parts":[[2022,2,4]],"date-time":"2022-02-04T11:35:17Z","timestamp":1643974517000},"page":"212","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":6,"title":["From Negative to Positive Diagnosis: Structural Variation Could Be the Second Mutation You Are Looking for in a Recessive Autosomal Gene"],"prefix":"10.3390","volume":"12","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2840-8844","authenticated-orcid":false,"given":"Ioanna","family":"Pyromali","sequence":"first","affiliation":[{"name":"Faculty of Medicine, MMNP (Maintenance My\u00e9linique et Neuropathies P\u00e9riph\u00e9riques), University of Limoges, EA6309, F-87000 Limoges, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nesrine","family":"Benslimane","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, MMNP (Maintenance My\u00e9linique et Neuropathies P\u00e9riph\u00e9riques), University of Limoges, EA6309, F-87000 Limoges, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3754-0070","authenticated-orcid":false,"given":"Fr\u00e9d\u00e9ric","family":"Favreau","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, MMNP (Maintenance My\u00e9linique et Neuropathies P\u00e9riph\u00e9riques), University of Limoges, EA6309, F-87000 Limoges, France"},{"name":"Centre Hospitalo-Universitaire (CHU) Limoges, Service de Biochimie et de G\u00e9n\u00e9tique Mol\u00e9culaire, F-87000 Limoges, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cyril","family":"Goizet","sequence":"additional","affiliation":[{"name":"Centre Hospitalo-Universitaire (CHU) Bordeaux-GH Pellegrin Tripode, Service de G\u00e9n\u00e9tique M\u00e9dicale, F-33076 Bordeaux, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Leila","family":"Lazaro","sequence":"additional","affiliation":[{"name":"Centre Hospitalier (CH) de la C\u00f4te Basque, F-64100 Bayonne, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Martine","family":"Vitry","sequence":"additional","affiliation":[{"name":"Centre Hospitalo-Universitaire (CHU) Limoges, Service de Biochimie et de G\u00e9n\u00e9tique Mol\u00e9culaire, F-87000 Limoges, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paco","family":"Derouault","sequence":"additional","affiliation":[{"name":"Centre Hospitalo-Universitaire (CHU) Limoges, Service de Bioinformatique, F-87000 Limoges, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6428-5162","authenticated-orcid":false,"given":"Franck","family":"Sturtz","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, MMNP (Maintenance My\u00e9linique et Neuropathies P\u00e9riph\u00e9riques), University of Limoges, EA6309, F-87000 Limoges, France"},{"name":"Centre Hospitalo-Universitaire (CHU) Limoges, Service de Biochimie et de G\u00e9n\u00e9tique Mol\u00e9culaire, F-87000 Limoges, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Corinne","family":"Magdelaine","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, MMNP (Maintenance My\u00e9linique et Neuropathies P\u00e9riph\u00e9riques), University of Limoges, EA6309, F-87000 Limoges, France"},{"name":"Centre Hospitalo-Universitaire (CHU) Limoges, Service de Biochimie et de G\u00e9n\u00e9tique Mol\u00e9culaire, F-87000 Limoges, France"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne-Sophie","family":"Lia","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, MMNP (Maintenance My\u00e9linique et Neuropathies P\u00e9riph\u00e9riques), University of Limoges, EA6309, F-87000 Limoges, France"},{"name":"Centre Hospitalo-Universitaire (CHU) Limoges, Service de Biochimie et de G\u00e9n\u00e9tique Mol\u00e9culaire, F-87000 Limoges, France"},{"name":"Centre Hospitalo-Universitaire (CHU) Limoges, Service de Bioinformatique, F-87000 Limoges, France"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2022,2,3]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2747","DOI":"10.1093\/bioinformatics\/bts526","article-title":"A robust model for read count data in exome sequencing experiments and implications for copy number variant calling","volume":"28","author":"Plagnol","year":"2012","journal-title":"Bioinformatics"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"13236","DOI":"10.18632\/oncotarget.7451","article-title":"Ioncopy: A novel method for calling copy number alterations in amplicon sequencing data including significance assessment","volume":"7","author":"Budczies","year":"2016","journal-title":"Oncotarget"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1586","DOI":"10.1093\/bioinformatics\/btx017","article-title":"\u2018COV\u2019COP\u2019 allows to detect CNVs responsible for inherited diseases among amplicons sequencing data","volume":"33","author":"Derouault","year":"2017","journal-title":"Bioinformatics"},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Derouault, P., Chauzeix, J., Rizzo, D., Miressi, F., Magdelaine, C., Bourthoumieu, S., Durand, K., Dzugan, H., Feuillard, J., and Sturtz, F. (2020). CovCopCan: An Efficient Tool to Detect Copy Number Variation from Amplicon Sequencing Data in Inherited Diseases and Cancer. PLoS Comput. Biol., 16.","DOI":"10.1371\/journal.pcbi.1007503"},{"key":"ref_5","doi-asserted-by":"crossref","unstructured":"Kang, Y., Nam, S.H., Park, K.S., Kim, Y., Kim, J.W., Lee, E., Ko, J.M., Lee, K.A., and Park, I. (2018). DeviCNV: Detection and visualization of exon-level copy number variants in targeted next-generation sequencing data. BMC Bioinform., 19.","DOI":"10.1186\/s12859-018-2409-6"},{"key":"ref_6","unstructured":"Adam, M.P., Ardinger, H.H., Pagon, R.A., Wallace, S.E., Bean, L.J., Mirzaa, G., and Amemiya, A. (2021). Charcot-Marie-Tooth (CMT) Hereditary Neuropathy Overview. GeneReviews\u00ae, University of Washington."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"219","DOI":"10.1016\/0092-8674(91)90613-4","article-title":"DNA Duplication Associated with Charcot-Marie-Tooth Disease Type 1","volume":"66","author":"Lupski","year":"1991","journal-title":"Cell"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"176","DOI":"10.1038\/ng0692-176","article-title":"Peripheral Myelin Protein-22 Gene Maps in the Duplication in Chromosome 17p11.2 Associated with Charcot-Marie-Tooth 1A","volume":"1","author":"Matsunami","year":"1992","journal-title":"Nat. Genet."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"166","DOI":"10.1038\/ng0692-166","article-title":"The Peripheral Myelin Gene PMP-22\/GAS-3 is Duplicated in Charcot-Marie-Tooth Disease Type 1A","volume":"1","author":"Valentijn","year":"1992","journal-title":"Nat. Genet."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"171","DOI":"10.1038\/ng0692-171","article-title":"The Peripheral Myelin Protein Gene PMP\u201322 Is Contained within the Charcot\u2013Marie\u2013Tooth Disease Type 1A Duplication","volume":"1","author":"Timmerman","year":"1992","journal-title":"Nat. Genet."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"706","DOI":"10.1136\/jnnp-2012-302451","article-title":"Charcot-Marie-Tooth Disease: Frequency of Genetic Subtypes and Guidelines for Genetic Testing","volume":"83","author":"Murphy","year":"2012","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1038\/s10038-019-0710-5","article-title":"Identification of novel pathogenic copy number variations in Charcot-Marie-Tooth disease","volume":"65","author":"Mortreux","year":"2020","journal-title":"J. Hum. Genet."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"4265","DOI":"10.1016\/j.csbj.2021.07.037","article-title":"New structural variations responsible for Charcot-Marie-Tooth disease: The first two large KIF5A deletions detected by CovCopCan software","volume":"19","author":"Pyromali","year":"2021","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"1106","DOI":"10.1086\/379525","article-title":"Mutations in a gene encoding a novel SH3\/TPR domain protein cause autosomal recessive Charcot-Marie-Tooth type 4C neuropathy","volume":"73","author":"Senderek","year":"2003","journal-title":"Am. J. Hum. Genet."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"17528","DOI":"10.1073\/pnas.0905523106","article-title":"SH3TC2\/KIAA1985 protein is required for proper myelination and the integrity of the node of Ranvier in the peripheral nervous system","volume":"106","author":"Arnaud","year":"2009","journal-title":"Proc. Natl. Acad. Sci. USA"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"1009","DOI":"10.1093\/hmg\/ddp565","article-title":"Mistargeting of SH3TC2 away from the recycling endosome causes Charcot-Marie-Tooth disease type 4C","volume":"19","author":"Roberts","year":"2010","journal-title":"Hum. Mol. Genet."},{"key":"ref_17","unstructured":"Adam, M.P., Ardinger, H.H., Pagon, R.A., Wallace, S.E., Bean, L.J.H., Mirzaa, G., and Amemiya, A. (1993). SH3TC2-Related Hereditary Motor and Sensory Neuropathy. GeneReviews\u00ae, University of Washington. Updated 11 March 2021."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"116376","DOI":"10.1016\/j.jns.2019.06.027","article-title":"Implication of the SH3TC2 gene in Charcot-Marie-Tooth disease associated with deafness and\/or scoliosis: Illustration with four new pathogenic variants","volume":"406","author":"Lerat","year":"2019","journal-title":"J. Neurol. Sci."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"873","DOI":"10.1136\/jnnp-2014-308826","article-title":"Inherited Neuropathies Consortium. CMT subtypes and disease burden in patients enrolled in the Inherited Neuropathies Consortium natural history study: A cross-sectional analysis","volume":"86","author":"Fridman","year":"2015","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"112","DOI":"10.1111\/j.1529-8027.2012.00382.x","article-title":"Characteristics of clinical and electrophysiological pattern of Charcot-Marie-Tooth 4C","volume":"17","author":"Yger","year":"2012","journal-title":"J. Peripher. Nerv. Syst."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1111\/j.1399-0004.2011.01640.x","article-title":"High frequency of SH3TC2 mutations in Czech HMSN I patients","volume":"80","author":"Mazanec","year":"2011","journal-title":"Clin. Genet."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"142","DOI":"10.1111\/jns.12175","article-title":"Screening for SH3TC2 gene mutations in a series of demyelinating recessive Charcot-Marie-Tooth disease (CMT4)","volume":"21","author":"Piscosquito","year":"2016","journal-title":"J. Peripher. Nerv. Syst."},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"2838","DOI":"10.1093\/brain\/awq270","article-title":"Aids to the investigation of peripheral nerve injuries. Medical Research Council: Nerve Injuries Research Committee. His Majesty\u2019s Stationery Office: 1942; pp. 48 (iii) and 74 figures and 7 diagrams; with aids to the examination of the peripheral nervous system. By Michael O\u2019Brien for the Guarantors of Brain. Saunders Elsevier: 2010; pp. [8] 64 and 94 Figures","volume":"133","author":"Compston","year":"2010","journal-title":"Brain"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"2095","DOI":"10.1016\/j.csbj.2020.07.021","article-title":"A mutation can hide another one: Think Structural Variants!","volume":"18","author":"Miressi","year":"2020","journal-title":"Comput. Struct. Biotechnol. J."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"371","DOI":"10.1002\/mus.25203","article-title":"Electrodiagnostic reference values for upper and lower limb nerve conduction studies in adult populations","volume":"54","author":"Chen","year":"2016","journal-title":"Muscle Nerve"}],"container-title":["Journal of Personalized Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2075-4426\/12\/2\/212\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T22:13:52Z","timestamp":1760134432000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2075-4426\/12\/2\/212"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,2,3]]},"references-count":25,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2022,2]]}},"alternative-id":["jpm12020212"],"URL":"https:\/\/doi.org\/10.3390\/jpm12020212","relation":{},"ISSN":["2075-4426"],"issn-type":[{"value":"2075-4426","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,2,3]]}}}