Genetic findings in ten Ecuadorian patients with suspected Wilson's disease

Wilson disease is a rare autosomal recessive disorder caused by variations in ATP7B, leading to copper accumulation and multisystemic damage. Diagnosis is often delayed due to its heterogeneous clinical presentation and limited genetic data in underrepresented populations.

We characterized ten Ecuadorian patients with clinical suspicion of Wilson disease using whole-exome sequencing (WES), selected to enable simultaneous assessment of ATP7B and other metabolic genes relevant to Wilson-like phenotypes. Variants were interpreted following HGNC and ACMG/AMP guidelines. Ancestry was examined in nine patients using ADMIXTURE and PCA with a reference panel of 968 individuals from African, European, and Indigenous American populations. ATP7B expression was quantified by RT-qPCR in the one patient lacking identifiable coding-region variants.

Six patients were homozygous and two were compound heterozygous for pathogenic or likely pathogenic ATP7B variants. The recurrent alleles c.2052dupC p.(Met685*) (Guayaquil) and c.2012_2013insAT p.(Met671Ilefs*) (Cañar/Cuenca) showed geographic and ancestry patterns consistent with known demographic structure in Ecuador, though not sufficient to infer founder effects. Additional variants included c.3188 C > T p.(Ala1603Val), c.3727 C > G p.(Leu1243Val), c.2318G > A p.(Cys773Tyr), and c.2080 C > T p.(Arg694Trp). One patient with no detectable ATP7B coding-region variation demonstrated ~ 9.8-fold reduced ATP7B expression, supporting the clinical diagnosis.

This study provides an integrated clinical, molecular, and ancestry framework for characterizing Wilson disease in an underrepresented population. The identification of regionally recurrent ATP7B variants, together with the diversity of clinical presentations, highlights the need for comprehensive diagnostic approaches in admixed populations. Larger studies incorporating segregation and functional assays will be essential to refine variant interpretation and improve access to molecular diagnosis in Latin America.