Biallelic SORD pathogenic variants cause Chinese patients with distal hereditary motor neuropathy

Abstract

Sorbitol dehydrogenase gene (SORD) has been identified as a novel causative gene of recessive forms of hereditary neuropathy, including Charcot–Marie–Tooth disease type 2 and distal hereditary motor neuropathy (dHMN). Our findings reveal two novel variants (c.404 A > G and c.908 + 1 G > C) and one known variant (c.757delG) within SORD in four Chinese dHMN families. Ex vivo cDNA polymerase chain reaction confirmed that c.908 + 1 G > C variant was associated with impaired splicing of the SORD transcript. In vitro cell functional studies showed that c.404 A > G variant resulted in aggregate formation of SORD and low protein solubility, confirming the pathogenicity of SORD variants. We have provided more evidence to establish SORD as a causative gene for dHMN.

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

“…These results were consistent with those from previous studies by members of the inherited neuropathies consortium (INC), which identified 45 individuals from 38 families in a cohort of over 1,000 families (4). Another recent study reported that the detection rate was 7.5% (3/40) in patients with CMT2 and 1.4% (3/215) in patients with CMT (5), while another study reported a detection rate of 13.8% (4/29) in patients with unclarified CMT2 and dHMN (6). Our findings provide valuable genetic and phenotypic information on the SORD gene in a large cohort of CMT and dHMN patients.…”

“…R299Ter. However, the mechanism is unclear with regard to patients with missense mutations (p.L10P, p.R110P, p.H135R, p.A153D, p.V322I) in previous studies (4,6) and those with the three missense mutations in our study (p.P244L, p. A259V, (17,18). Drosophila has two functional SORD proteins that are 75 and 73% identical to the human SORD protein, and Drosophila melanogaster models of SORD deficiency could not fully mimic the pathogenesis of SORD-related neuropathy, especially sensory nerve impairment.…”

“…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).…”

Identification of Novel Genomic-Variant Patterns of OR56A5, OR52L1, and CTSD in Retinitis Pigmentosa Patients by Whole-Exome Sequencing

“…Genome-wide association studies that focus on detecting risk variants for gene discovery and precision medicine can predict disease risk for an individual. Taiwan Biobank owns the largest publicly available genetic database of individuals with East Asian ancestry [ 52 ] and has the unique sequencing chips focusing on healthy and subhealth populations as well as several disease cohorts. We identified RP-associated variants that greatly improved the coverage of SNP genotyping data.…”

From Stem Cells to Populations—Using hiPSC, Next-Generation Sequencing, and GWAS to Explore the Genetic and Molecular Mechanisms of Congenital Heart Defects

“…All detected single nucleotide variants (SNV) were in the coding DNA or in splice sites and therefore could have been detectable also by WES. Another WGS study of 24 critically ill newborn infants with CHD and other malformations identified a definitive or likely genetic diagnosis in 11 patients [ 38 ]. Some of the probands were also tested with chromosomal microarray and targeted gene panels recommended by their primary medical team.…”