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

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

Julia Grzybowska-Adamowicz  1 , Karolina Gadzalska  1 , Paulina Jakiel  1 , Ewa Juścińska  1 , Monika Gorządek  1 , Sebastian Skoczylas  1 , Tomasz Płoszaj  1 , Przemysława Jarosz-Chobot  2 , Irina Kowalska  3 , Małgorzata Myśliwiec  4 , Agnieszka Szadkowska  5 , Agnieszka Zmysłowska  1
Affiliations

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

Julia Grzybowska-Adamowicz et al. Genes (Basel). .

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.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Pedigree of family #6 with two coexisting monogenic diabetes. Mutation in GJB2 gene (blue), mutation in GCK gene (green), mutation in WFS1 gene (orange).
Figure 2
Figure 2
Genotype–phenotype correlations between WFS1 gene variants and clinical manifestations.
See this image and copyright information in PMC

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