An incidental heterozygous ATP7B nonsense variant leading to a diagnostic pitfall for Wilson disease: a pediatric...

Wilson disease (WD) is an autosomal recessive disorder caused by pathogenic variants in ATP7B, resulting in impaired copper transport and progressive copper accumulation, most prominently affecting the liver. With the growing use of genetic testing, incidental detection of ATP7B pathogenic/likely pathogenic variants in individuals without typical hepatic phenotypes can prompt overdiagnosis and unnecessary investigations. This case highlights the importance of interpreting a single heterozygous ATP7B variant in the context of phenotype and a standardized biochemical diagnostic pathway for WD.

A 13-year-old Han Chinese boy presented with recurrent brief paroxysmal attacks for > 1 year, markedly worsened over the preceding month. Episodes were triggered by rising from sitting, characterized by transient postural instability with unilateral head deviation and ipsilateral dystonic/choreiform movements, lasted ~ 10 s, and resolved spontaneously. Consciousness was preserved, with no incontinence, convulsions, or postictal symptoms. Interictal neurological examination was normal. Ambulatory EEG monitoring captured three typical attacks without epileptiform discharges or ictal EEG correlates, and brain MRI was unremarkable. A slit-lamp examination revealed no Kayser-Fleischer ring. A low serum copper level (9.43 µmol/L; reference 10.50-29.90) prompted further evaluation; genetic testing incidentally identified a heterozygous ATP7B variant (NM_000053.4:c.2851 C > T; p.Gln951Ter), reported as likely pathogenic. WD was considered. However, ceruloplasmin was normal (231.6 mg/L; reference 200.0-420.0 mg/L), ceruloplasmin oxidase activity measured by the p-phenylenediamine method was normal (0.372 OD; reference > 0.200 OD), liver biochemistry was normal (ALT 11 U/L, AST 16 U/L, GGT 14 U/L; bilirubin within reference range), and abdominal ultrasound showed a normal liver and biliary tree. Crucially, a follow-up quantitative 24-hour urinary copper test was strictly normal, and parental segregation analysis confirmed that the ATP7B variant represented a paternally inherited heterozygous state without biochemical evidence of Wilson disease, making active Wilson disease highly unlikely.

This case illustrates a critical diagnostic pitfall: incidental heterozygous ATP7B variants can trigger severe diagnostic anchoring bias. To prevent overdiagnosis, genetic findings must be subordinated to strict phenotype-driven evaluations, formal Leipzig scoring, and definitive biochemical gold standards.