The Presence of Wnt Signaling Mutations in Patients With Diabetic Retinopathy

Purpose: The relationship between poor hemoglobin A1c (HbA1c) control and risk of proliferative diabetic retinopathy (PDR) is well known. Nevertheless, some patients have discordant disease (controlled HbA1c and severe PDR or vice versa). One potential explanation for this discrepancy is the presence of underlying genetic mutations in the Wingless-related integration site (Wnt) signaling pathway. However, minimal clinical data exist on the presence of Wnt signaling mutations in patients with diabetes mellitus (DM) and the correlation with diabetic retinopathy. Methods: Retrospective, nonconsecutive case review of patients with type 1 or 2 DM who underwent genetic testing for at least 1 recognized Wnt signaling pathway mutation from 2011 to 2016. The clinical course and retinal images were reviewed for patients with identifiable mutations. Results: Thirty-six patients, ages 13 to 79 years, consented for genetic analysis. Three patients (8.3%) exhibited at least 1 recognized genetic mutation in the Wnt signaling pathway. Case 1 was a 65-year-old female with type 1 diabetes for > 20 years, HbA1c <7.0%, and no findings of diabetic retinopathy (Tetraspanin 12). Case 2 was a 13-year-old male with type 1 diabetes for 8 years, moderate HbA1c control (7.6-8.3%), and absence of diabetic retinopathy (Norrin). Case 3 was a 48-year-old male with severe PDR requiring multiple laser and antivascular endothelial growth factor (anti-VEGF) treatments despite well-controlled HbA1c (6.0%) (Frizzled-4). Conclusion: Wnt signaling pathway mutations exist in patients with DM. Further studies investigating the prevalence and clinical significance of these mutations in a larger diabetic population are warranted. Identification of these patients with genetic testing may enable earlier medical intervention.