New data reveals most previously unexplained Wilson disease cases are due to overlooked variants in the ATP7B gene. Wilson disease (WD) is a rare inherited disorder where impaired ATP7B copper transport protein function causes copper accumulation, affecting the liver and brain. Delayed diagnosis worsens outcomes.
In a study of 761 WD patients, 5.8% had few or no identified ATP7B variants despite meeting diagnostic criteria. Advanced genomic and functional tools resolved over half these ambiguous cases, finding no evidence of other genetic causes. Whole genome sequencing and variant reclassification identified pathogenic ATP7B variants in 52% of genetically unresolved patients. ATP7B peptide analysis further supported the role of uncertain variants in six additional patients. These methods confirmed ATP7B dysfunction in 66% of previously unresolved cases, leading to genetic confirmation in 98% of the entire cohort.
Screening of nearly 100 copper-related genes and over 4,000 genes linked to liver or neurological disorders found no alternative genetic explanations. The findings reinforce WD as a single-gene disorder driven by ATP7B. Clinicians should routinely re-evaluate genetic findings using contemporary sequencing methods and functional assays for patients with strong clinical suspicion but inconclusive genetic results. This improves diagnostic certainty, facilitates genetic counseling, and enables cascade testing in families.