Undiagnosed wilson disease in cryptogenic cirrhosis: a genetic study

Wilson disease is a rare autosomal recessive disorder caused by copper accumulation, primarily affecting the liver and brain. While genetic estimates suggest a global prevalence of 13.9-15.4 per 100,000 individuals, clinical diagnoses are significantly lower, raising concerns of underdiagnosis. We aimed to investigate the presence of undiagnosed Wilson Disease in patients who underwent liver transplantation for cryptogenic liver disease at a large transplantation center.

This observational study analyzed adult patients transplanted for cryptogenic liver disease at La Fe University Hospital (1991-2023). Comprehensive clinical, biochemical, and imaging assessments were used to exclude known liver diseases. ATP7B gene sequencing-including all exons, flanking introns, and the promoter region-was performed using Sanger sequencing. Variant interpretation was conducted using ClinVar, HGMD, GERP, CADD, REVEL, PolyPhen-2, and gnomAD.

Among 2708 patients, 17 fulfilled the criteria for cryptogenic liver disease. Twenty-two distinct ATP7B single nucleotide variants were identified. None were classified as pathogenic. One novel variant (c.256A>C) was detected, but its pathogenicity could not be confirmed. No conclusive evidence of undiagnosed Wilson Disease was found in the cohort.

Despite higher genetic prevalence estimates, this study did not identify undiagnosed Wilson Disease cases among liver transplant recipients with cryptogenic liver disease, suggesting a low prevalence of missed diagnoses in this clinical setting. Larger, multicenter studies are warranted to explore the potential underdiagnosis of Wilson Disease in broader populations.