Recently, biallelic variants in the SORD gene were identified as causal for axonal hereditary neuropathy (HN). We ascertained the spectrum and frequency of SORD variants among a large cohort of Czech patients with unknown cause of HN. Exome sequencing data were analysed for SORD (58 patients). The prevalent c.757del variant was tested with fragment analysis (931 patients). Sanger sequencing in additional 70 patients was done. PCR primers were designed to amplify the SORD gene with the exclusion of the pseudogene SORD2P. Sequence differences between gene and pseudogene were identified and frequencies of SNPs were calculated. Eighteen patients from 16 unrelated families with biallelic variants in the SORD gene were found and the c.757del was present in all patients on at least one allele. Three novel, probably pathogenic, variants were detected, always in a heterozygous state in combination with the c.757del on the second allele. Patients presented with a slowly progressive axonal HN. Almost all patients had moderate pes cavus deformity. SORD neuropathy is frequent in Czech patients and the third most common cause of autosomal recessive HN. The c.757del is highly prevalent. Specific amplification of the SORD gene with the exclusion of the pseudogene is essential for a precise molecular diagnostics.

Department of Neurology 2nd Faculty of Medicine and University Hospital Motol Prague Czech Republic

Department of Paediatric Neurology 2nd Faculty of Medicine and University Hospital Motol Prague Czech Republic

Neurogenetic Laboratory Department of Paediatric Neurology 2nd Faculty of Medicine and University Hospital Motol Prague Czech Republic

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Reilly MM. Classification and diagnosis of the inherited neuropathies. Ann. Indian Acad. Neurol. 2009;12:80–88. doi: 10.4103/0972-2327.53075. PubMed DOI PMC

Timmerman V, Strickland AV, Zuchner S. Genetics of Charcot-Marie-tooth (CMT) disease within the frame of the human genome project success. Genes (Basel) 2014;5:13–32. doi: 10.3390/genes5010013. PubMed DOI PMC

Mendoza-Ferreira N, Karakaya M, Cengiz N, Beijer D, Brigatti KW, Gonzaga-Jauregui C, Fuhrmann N, Holker I, Thelen MP, Zetzsche S, Rombo R, Puffenberger EG, De Jonghe P, Deconinck T, Zuchner S, Strauss KA, Carson V, Schrank B, Wunderlich G, Baets J, Wirth B. De Novo and inherited variants in GBF1 are associated with axonal neuropathy caused by golgi fragmentation. Am. J. Hum. Genet. 2020;107:763–777. doi: 10.1016/j.ajhg.2020.08.018. PubMed DOI PMC

Cortese A, Zhu Y, Rebelo AP, Negri S, Courel S, Abreu L, Bacon CJ, Bai Y, Bis-Brewer DM, Bugiardini E, Buglo E, Danzi MC, Feely SME, Athanasiou-Fragkouli A, Haridy NA, Inherited Neuropathy C, Isasi R, Khan A, Laura M, Magri S, Pipis M, Pisciotta C, Powell E, Rossor AM, Saveri P, Sowden JE, Tozza S, Vandrovcova J, Dallman J, Grignani E, Marchioni E, Scherer SS, Tang B, Lin Z, Al-Ajmi A, Schule R, Synofzik M, Maisonobe T, Stojkovic T, Auer-Grumbach M, Abdelhamed MA, Hamed SA, Zhang R, Manganelli F, Santoro L, Taroni F, Pareyson D, Houlden H, Herrmann DN, Reilly MM, Shy ME, Zhai RG, Zuchner S. Biallelic mutations in SORD cause a common and potentially treatable hereditary neuropathy with implications for diabetes. Nat. Genet. 2020;52:473–481. doi: 10.1038/s41588-020-0615-4. PubMed DOI PMC

Azzedine H, Zavadakova P, Plante-Bordeneuve V, Vaz Pato M, Pinto N, Bartesaghi L, Zenker J, Poirot O, Bernard-Marissal N, Arnaud Gouttenoire E, Cartoni R, Title A, Venturini G, Medard JJ, Makowski E, Schols L, Claeys KG, Stendel C, Roos A, Weis J, Dubourg O, Leal Loureiro J, Stevanin G, Said G, Amato A, Baraban J, LeGuern E, Senderek J, Rivolta C, Chrast R. PLEKHG5 deficiency leads to an intermediate form of autosomal-recessive Charcot-Marie-Tooth disease. Hum. Mol. Genet. 2013;22:4224–4232. doi: 10.1093/hmg/ddt274. PubMed DOI PMC

Senderek J, Bergmann C, Stendel C, Kirfel J, Verpoorten N, De Jonghe P, Timmerman V, Chrast R, Verheijen MH, Lemke G, Battaloglu E, Parman Y, Erdem S, Tan E, Topaloglu H, Hahn A, Muller-Felber W, Rizzuto N, Fabrizi GM, Stuhrmann M, Rudnik-Schoneborn S, Zuchner S, Michael Schroder J, Buchheim E, Straub V, Klepper J, Huehne K, Rautenstrauss B, Buttner R, Nelis E, Zerres K. Mutations in a gene encoding a novel SH3/TPR domain protein cause autosomal recessive Charcot-Marie-Tooth type 4C neuropathy. Am. J. Hum. Genet. 2003;73:1106–1119. doi: 10.1086/379525. PubMed DOI PMC

Elmas M, Yildiz H, Erdogan M, Gogus B, Avci K, Solak M. Comparison of clinical parameters with whole exome sequencing analysis results of autosomal recessive patients; a center experience. Mol. Biol. Rep. 2019;46:287–299. doi: 10.1007/s11033-018-4470-7. PubMed DOI

Karczewski KJ, Francioli LC, Tiao G, Cummings BB, Alfoldi J, Wang Q, Collins RL, Laricchia KM, Ganna A, Birnbaum DP, Gauthier LD, Brand H, Solomonson M, Watts NA, Rhodes D, Singer-Berk M, England EM, Seaby EG, Kosmicki JA, Walters RK, Tashman K, Farjoun Y, Banks E, Poterba T, Wang A, Seed C, Whiffin N, Chong JX, Samocha KE, Pierce-Hoffman E, Zappala Z, O'Donnell-Luria AH, Minikel EV, Weisburd B, Lek M, Ware JS, Vittal C, Armean IM, Bergelson L, Cibulskis K, Connolly KM, Covarrubias M, Donnelly S, Ferriera S, Gabriel S, Gentry J, Gupta N, Jeandet T, Kaplan D, Llanwarne C, Munshi R, Novod S, Petrillo N, Roazen D, Ruano-Rubio V, Saltzman A, Schleicher M, Soto J, Tibbetts K, Tolonen C, Wade G, Talkowski ME. The mutational constraint spectrum quantified from variation in 141,456 humans. Nature. 2020;581:434–443. doi: 10.1038/s41586-020-2308-7. PubMed DOI PMC

Lassuthova P, Beharka R, Krutova M, Neupauerova J, Seeman P. COX6A1 mutation causes axonal hereditary motor and sensory neuropathy: The confirmation of the primary report. Clin. Genet. 2016;89:512–514. doi: 10.1111/cge.12649. PubMed DOI

Lassuthova P, Brozkova DS, Krutova M, Neupauerova J, Haberlova J, Mazanec R, Dvorackova N, Goldenberg Z, Seeman P. Mutations in HINT1 are one of the most frequent causes of hereditary neuropathy among Czech patients and neuromyotonia is rather an underdiagnosed symptom. Neurogenetics. 2015;16:43–54. doi: 10.1007/s10048-014-0427-8. PubMed DOI

Lassuthova P, Mazanec R, Vondracek P, Siskova D, Haberlova J, Sabova J, Seeman P. High frequency of SH3TC2 mutations in Czech HMSN I patients. Clin. Genet. 2011;80:334–345. doi: 10.1111/j.1399-0004.2011.01640.x. PubMed DOI

Lassuthova P, Siskova D, Haberlova J, Sakmaryova I, Filous A, Seeman P. Congenital cataract, facial dysmorphism and demyelinating neuropathy (CCFDN) in 10 Czech Gypsy children–frequent and underestimated cause of disability among Czech Gypsies. Orphanet J. Rare Dis. 2014;9:46. doi: 10.1186/1750-1172-9-46. PubMed DOI PMC

Safka Brozkova D, Paulasova Schwabova J, Neupauerova J, Sabova J, Krutova M, Perina V, Trkova M, Lassuthova P, Seeman P. HMSN Lom in 12 Czech patients, with one unusual case due to uniparental isodisomy of chromosome 8. J. Hum. Genet. 2017;62:431–435. doi: 10.1038/jhg.2016.148. PubMed DOI

Chen X, Wan L, Wang W, Xi WJ, Yang AG, Wang T. Re-recognition of pseudogenes: From molecular to clinical applications. Theranostics. 2020;10:1479–1499. doi: 10.7150/thno.40659. PubMed DOI PMC

Xu J, Zhang J. Are human translated pseudogenes functional? Mol. Biol. Evol. 2016;33:755–760. doi: 10.1093/molbev/msv268. PubMed DOI PMC

Sommer R, Tautz D. Minimal homology requirements for PCR primers. Nucleic Acids Res. 1989;17:6749. doi: 10.1093/nar/17.16.6749. PubMed DOI PMC

Claes KB, De Leeneer K. Dealing with pseudogenes in molecular diagnostics in the next-generation sequencing era. Methods Mol. Biol. 2014;1167:303–315. doi: 10.1007/978-1-4939-0835-6_21. PubMed DOI

DePristo MA, Banks E, Poplin R, Garimella KV, Maguire JR, Hartl C, Philippakis AA, del Angel G, Rivas MA, Hanna M, McKenna A, Fennell TJ, Kernytsky AM, Sivachenko AY, Cibulskis K, Gabriel SB, Altshuler D, Daly MJ. A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat. Genet. 2011;43:491–498. doi: 10.1038/ng.806. PubMed DOI PMC

Van der Auwera GA, Carneiro MO, Hartl C, Poplin R, Del Angel G, Levy-Moonshine A, Jordan T, Shakir K, Roazen D, Thibault J, Banks E, Garimella KV, Altshuler D, Gabriel S, DePristo MA. From FastQ data to high confidence variant calls: The Genome Analysis Toolkit best practices pipeline. Curr. Protoc. Bioinform. 2013;43:111011–111033. doi: 10.1002/0471250953.bi1110s43. PubMed DOI PMC

Yuan RY, Ye ZL, Zhang XR, Xu LQ, He J. Evaluation of SORD mutations as a novel cause of Charcot-Marie-Tooth disease. Ann. Clin. Transl. Neurol. 2021;8:266–270. doi: 10.1002/acn3.51268. PubMed DOI PMC

Dong HL, Li JQ, Liu GL, Yu H, Wu ZY. Biallelic SORD pathogenic variants cause Chinese patients with distal hereditary motor neuropathy. NPJ Genom. Med. 2021;6:1. doi: 10.1038/s41525-020-00165-6. PubMed DOI PMC

Frasquet M, Rojas-Garcia R, Argente-Escrig H, Vazquez-Costa JF, Muelas N, Vilchez JJ, Sivera R, Millet E, Barreiro M, Diaz-Manera J, Turon-Sans J, Cortes-Vicente E, Querol L, Ramirez-Jimenez L, Martinez-Rubio D, Sanchez-Monteagudo A, Espinos C, Sevilla T, Lupo V. Distal hereditary motor neuropathies: Mutation spectrum and genotype-phenotype correlation. Eur. J. Neurol. 2020 doi: 10.1111/ene.14700. PubMed DOI

Yonghzie X, et al. Genetic and clinical features in 24 chinese distal hereditary motor neuropathy families. Front. Neurol. 2020;11:603003. doi: 10.3389/fneur.2020.603003. PubMed DOI PMC