The Valdivia Project: genetic characterization of a unique Wolfram Syndrome cluster in coastal Ecuador

Abstract Objective This study aims to document the first genetically confirmed cases of WS1 in Ecuador. Design and methods A Cross-Sectional study was conducted among individuals with early-onset insulin-dependent diabetes, residing in Santa Elena Province, Ecuador. A detailed clinical history and family tree were obtained along with laboratory and imaging diagnostics. A genetic whole exome sequencing was performed to confirm WS1 or not (NWS). Results This Ecuadorian cohort included 38 participants (19 males) aged < 35 years with an average diabetes onset at 3 years old. Approximately 50% of the patients are related by consanguinity. Genetic studies tested positive for WS1 in 26 (69%) patients, which yields a prevalence of 1/12,000 inhabitants and the presence of two previously undescribed variants located in exon 8. Twenty-three were homozygous. Positive antibody testing was reported in 3/26 WS1 and in 4/11 NWS patients. High prevalence of severe and early neurological complications: optic atrophy, deafness and urinary disorders were documented. No patient had diabetes insipidus. Conclusions Findings suggest the highest WS1 prevalence worldwide and two novel WS1 variants. There is high consanguinity and frequency of severe, early clinical complications among WS1 patients. In addition, only 11% were diagnosed with type 1 diabetes, suggesting that younger patients with early-onset, non-autoimmune diabetes should undergo comprehensive genetic testing.