Patients with a Wide Range of Disorders Related to WFS1 Gene Variants: Novel Mutations and Genotype-Phenotype Correlations

Genes (Basel). 2024 Dec 12;15(12):1592. doi: 10.3390/genes15121592.

Abstract

Background:WFS1-spectrum disorders are caused by a mutation in the WFS1 gene. The term includes a wide range of rare disorders, from the most severe Wolfram syndrome with autosomal recessive inheritance to milder clinical manifestations with a single causative variant in the WFS1 gene, such as Wolfram-like syndrome, low-frequency sensorineural hearing loss (LFSNHL), isolated diabetes mellitus (DM), nonsyndromic optic atrophy (OA), and isolated congenital cataracts. Methods: The aim of this study was to evaluate genotype-phenotype correlations in Polish patients with WFS1-spectrum disorders. The study group constituted 22 patients (10 F; 12 M), including 10 patients (3 F; 7 M) referred to the Outpatient Clinic for Rare Diseases in Children and Adolescents and Diabetogenetics between 2019 and 2024 with clinical symptoms suggestive of WFS1-spectrum disorders, and 12 of their first-degree relatives (7 F; 5 M) from 10 families in Poland. Molecular testing was performed using tNGS (Targeted Next Generation Sequencing; Illumina) and analyzed for variants in the WFS1 gene. Results: Thirteen different variants in the WFS1 gene were found in 22 individuals (10 patients and family members), including the identification of two new variants (c.1535T>C and c.2485C>G). All patients had hyperglycemia or DM, hearing impairment, OA, or a combination of these symptoms. Four patients in the study group were diagnosed with Wolfram syndrome and all were compound heterozygotes for variants in the WFS1 gene. Conclusions: The evaluation of molecular characteristics in combination with clinical symptoms broadens the understanding of WFS1-spectrum disorders and allows more accurate management and prognosis for patients with this diagnosis.

Keywords: WFS1-spectrum disorders; Wolfram syndrome; Wolfram-like syndrome; genotype–phenotype correlation.

MeSH terms

  • Adolescent
  • Adult
  • Cataract / genetics
  • Cataract / pathology
  • Child
  • Child, Preschool
  • Diabetes Mellitus / genetics
  • Female
  • Genetic Association Studies*
  • Hearing Loss, Sensorineural* / genetics
  • Humans
  • Infant
  • Male
  • Membrane Proteins* / genetics
  • Mutation*
  • Optic Atrophy / genetics
  • Optic Atrophy / pathology
  • Pedigree
  • Phenotype
  • Poland
  • Wolfram Syndrome* / genetics
  • Young Adult

Substances

  • wolframin protein
  • Membrane Proteins

Grants and funding

This research received no external funding.