Biallelic variants in the SORD gene are one of the most common causes of hereditary neuropathy among Czech patients

Abstract

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.

Long read sequencing overcomes challenges in the diagnosis of SORD neuropathy

“…This discovery was further replicated in CMT patient cohorts in the Czech Republic, 4 Spain, 5 and China 6‐8 . Typically, affected individuals carry the nonsense SORD c.757del variant (rs1042079) in a homozygous or compound heterozygous state, leading to a loss of SORD function 3‐8 …”

“…Our novel use of ONT long‐read sequencing confirmed that these variants were biallelic and were present in the SORD gene, rather than the homologous pseudogene SORD2P . Whilst previous cohort studies identified biallelic SORD mutations affecting 3‐10% of the CMT2/dHMN cohort, 3‐8 we identified a single individual from 97 exomes of individuals with a clinical CMT2/dHMN diagnosis (1.0%). Although this may represent the true frequency of biallelic SORD mutations in our Australian cohort, it has been speculated that commonly used next‐generation sequencing pipelines are unable to accurately detect SORD c.757del due to the SORD2P gene 3 .…”

“…Recently, recessive mutations in the SORD gene (15q21.1) were identified as a common cause of CMT2 and distal hereditary motor neuropathy (dHMN) in a large multicenter cohort of inherited neuropathy patients 3 . This discovery was further replicated in CMT patient cohorts in the Czech Republic, 4 Spain, 5 and China 6‐8 . Typically, affected individuals carry the nonsense SORD c.757del variant (rs1042079) in a homozygous or compound heterozygous state, leading to a loss of SORD function 3‐8 …”

Clinical and Genetic Features of Biallelic Mutations in SORD in a Series of Chinese Patients With Charcot-Marie-Tooth and Distal Hereditary Motor Neuropathy

“…Since biallelic mutations in the sorbitol dehydrogenase (SORD) gene were first described in May 2020, 14 mutations have been identified to our knowledge (4)(5)(6)(7). SORD-related neuropathy has been reported as one of the most frequent causes of autosomal recessive CMT2 and dHMN (4).…”

“…SORD -related neuropathy has been reported as one of the most frequent causes of autosomal recessive CMT2 and dHMN ( 4 ). The prevalent mutation is c.757delG (p.A253Qfs * 27), and almost all previously reported mutations in patients with CMT and dHMN are related to this variant, either in homozygous or heterozygous states ( 4 , 5 , 7 ), except one Chinese patient with dHMN harboring the compound heterozygous c.404 A>G and c.9081 + G>C mutation ( 6 ). Most of the mutations in SORD are frameshift or splicing mutations, indicating a loss of function of sorbitol dehydrogenase, which is a key enzyme that converts sorbitol to fructose.…”