ClinVar

In affected individuals from 30 unrelated families with autosomal recessive distal hereditary motor neuronopathy-8 (HMNR8; 618912), also known as SORD deficiency with peripheral neuropathy (SORDD), Cortese et al. (2020) identified a homozygous 1-bp deletion (c.757delG, NM_003104.6) in exon 7 of the SORD gene, predicted to result in a frameshift and premature termination (Ala253GlnfsTer27) in the tetramer interface of the protein. Segregation of the variant was confirmed in only a few families in which the affected offspring inherited the variants from heterozygous unaffected parents, and only a few families had more than 1 affected individual. The mutation was found by whole-exome or whole-genome sequencing and confirmed by Sanger sequencing. The variant was present in 623 of 142,588 genomes in the gnomAD database (frequency of 0.004). Cortese et al. (2020) noted that SORD has a nonfunctional highly homologous paralog, the pseudogene SORD2 or SORD2P: the c.757delG variant is present in SORD2 in over 95% of control chromosomes. The authors used Sanger sequencing to confirm that the c.757delG mutation identified in their patients occurred in the SORD gene. Fibroblasts derived from 4 patients who were homozygous for the c.757delG variant showed absence of the SORD protein and a 10-fold increase in intracellular sorbitol compared to controls. Treatment of patient fibroblasts with aldose reductase inhibitors reduced intracellular sorbitol levels. Additional functional studies of the specific variants were not performed. Serum levels of sorbitol were over 100 times higher in 10 patients with the homozygous variant compared to controls. Eight additional patients, including 2 sibs (family 14), with a similar phenotype were compound heterozygous for c.757delG and another SORD variant. The other alleles included R299X (182500.0002), R110P, R100X, A153D, V322I, L10F, and an intragenic deletion (c.316_425+165del). Familial segregation of these variants could be demonstrated in only 2 patients (patients 4 and 37); familial segregation could not be conclusively demonstrated in the other patients. Several of these variants were present in the gnomAD database at a low frequency (less than 0.0001). All patients were ascertained from 3 large cohorts totaling about 1,000 individuals with peripheral neuropathy who underwent whole-exome or whole-genome sequencing.

In 2 unrelated Chinese patients (patients 1 and 2) with SORDD, Liu et al. (2021) identified homozygosity for the c.757delG mutation in the SORD gene. The mutation, which was identified by whole-exome sequencing, was identified in the carrier state in both sets of parents. The mutation was present at a frequency of 0.0046 in 650 Han Chinese healthy individuals and at a frequency of 0.002 in the Asian population in the gnomAD database (v3.0); it was not present in the 1000 Genomes Project database. In 3 additional unrelated Chinese patients with SORDD, Liu et al. (2021) identified compound heterozygosity for the c.757delG mutation with another mutation in the SORD gene: a c.776C-T transition, resulting in an ala259-to-val (A259V; 182500.0003) substitution, in patient 3; a c.731C-T transition, resulting in a pro244-to-leu (182500.0004) substitution, in patient 4; and a c.851T-C transition, resulting in a leu284-to-pro (L284P; 182500.0005) substitution, in patient 5. The parents in each case were carriers. The missense variants in patients 3, 4, and 5 occurred at highly conserved residues and had a minor allele frequency of less than 0.00001 in gnomAD (v3.0). All 3 variants were classified as likely pathogenic according to ACMG guidelines.