Combined clinical and genomic analysis uncovers neonatal-onset Wilson disease in two siblings with idiopathic...

Wilson's disease is an autosomal recessive disorder related to genetic defects in ATP7B gene and characterized by a hepatic and/or neurological impairment. This disease is often misdiagnosed on due to its phenotypic heterogeneity, supporting the importance of the genetic testing. In our study, we reported two brothers presenting with a chronic hepatopathy, classified as intrahepatic cholestasis with unknown etiology based on clinical explorations. A molecular screening through Whole-exome-sequencing was conducted, followed by sanger sequencing and co-segregation analysis in the family's members. Generated data were the subject of in silico analysis. Results revealed two pathogenic heterozygous variants in ATP7B gene (p.Met665Ile/ p.Gly869Arg) in compound heterozygous state in the analyzed proband and his brother. Predictive data supported their effect on the stability at the RNA and protein levels. In line of these data, additional clinical explorations were ensured and the Leipzig score was assessed to establish the WD diagnosis. Moreover, we identified two additional heterozygous variants shared by both siblings in CFTR (p.Thr351Ser) and PEX26 (p.Leu153Val), which may act as phenotype modifiers. Notably, both patients exhibited exocrine pancreatic insufficiency, raising the possibility of a contributory role for the CFTR variant in this atypical presentation. In conclusion, our study reveals a complex genetic background involving ATP7B, CFTR, and PEX26. While the ATP7B variants are responsible for WD, the additional variants may influence the age of onset and severity of the clinical phenotype. These findings underscore the value of high-throughput sequencing technologies in uncovering the molecular basis and phenotypic complexity of inherited diseases.