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

<b>Background:</b><i>WFS1</i>-spectrum disorders are caused by a mutation in the <i>WFS1</i> 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 <i>WFS1</i> gene, such as Wolfram-like syndrome, low-frequency sensorineural hearing loss (LFSNHL), isolated diabetes mellitus (DM), nonsyndromic optic atrophy (OA), and isolated congenital cataracts. <b>Methods:</b> The aim of this study was to evaluate genotype-phenotype correlations in Polish patients with <i>WFS1</i>-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 <i>WFS1</i>-spectrum disorders, and 12 of their first-degree relatives (7 F; 5 M) from 10 families in Poland. Molecular testing was performed using tNGS (<i>Targeted Next Generation Sequencing</i>; Illumina) and analyzed for variants in the <i>WFS1</i> gene. <b>Results</b>: Thirteen different variants in the <i>WFS1</i> 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 <i>WFS1</i> gene. <b>Conclusions:</b> The evaluation of molecular characteristics in combination with clinical symptoms broadens the understanding of <i>WFS1</i>-spectrum disorders and allows more accurate management and prognosis for patients with this diagnosis.