Wilson Disease Remains a Single-Gene Disorder : JHEP Reports | May 2026

Introduction

Wilson disease (WD) is an autosomal recessive copper metabolism disorder caused by pathogenic variants in the ATP7B gene. Although genetic confirmation is increasingly incorporated into diagnostic algorithms, up to 20% of clinically diagnosed patients in historical cohorts remained genetically unresolved despite strong clinical evidence of WD. This multicenter international study evaluated whether modern genomic and functional approaches could clarify the molecular basis of these unresolved cases and determine whether WD truly represents a single-gene disorder.

Problem Statement

Conventional sequencing strategies, including hotspot analysis and Sanger sequencing, frequently fail to identify all pathogenic ATP7B variants. This diagnostic gap has generated speculation regarding alternative genetic causes, modifier genes or genetically heterogeneous Wilson-like syndromes. Uncertainty in unresolved cases complicates diagnostic confidence, family screening and genetic counselling, particularly when clinical Leipzig scores strongly support WD despite incomplete molecular confirmation.

Summary

This international multicenter study analyzed 761 clinically confirmed WD patients from tertiary referral centers in Germany, USA, Spain and Denmark. Among the cohort, only 44 patients (5.8%) had zero or one previously identified pathogenic ATP7B variant despite definite clinical WD. A comprehensive five-step diagnostic strategy incorporating whole genome sequencing (WGS), expanded gene panel analysis, long-read sequencing and ATP7B peptide quantification was applied to these unresolved cases.

Reanalysis of ATP7B alone resolved 52% of previously unexplained cases. Seven patients were solved through reinterpretation of previously reported variants of uncertain significance, while 16 additional patients were diagnosed after WGS identified previously undetected ATP7B variants, including intronic, structural and complex rearrangements missed by earlier sequencing methodologies. Overall, 11 novel ATP7B variants were identified. Functional ATP7B peptide analysis further confirmed protein dysfunction in additional unresolved patients, increasing the diagnostic confirmation rate to 66% within the genetically unresolved subgroup and to 98% across the entire WD cohort.

Importantly, extensive screening of 97 copper metabolism-related genes and more than 4,300 genes associated with hepatic or neurological disorders failed to identify alternative monogenic causes of disease. Even advanced long-read sequencing approaches did not reveal non-ATP7B pathogenic mechanisms. These findings strongly reinforce the concept that WD is fundamentally a single-gene disorder caused by ATP7B dysfunction rather than a genetically heterogeneous syndrome.

The study has major clinical implications. It demonstrates that many historically “genetically negative” WD cases reflect limitations of older sequencing technologies or outdated variant classification rather than alternative disease biology. The authors advocate routine re-evaluation of unresolved WD cases using contemporary WGS, comprehensive ATP7B analysis and functional peptide assays before considering alternative diagnoses. This strategy can substantially improve diagnostic certainty, cascade family testing and personalized clinical management in WD.