Exploring the pathogenesis of a compound heterozygous variant in ATP7B associated with Wilson disease in an Iranian...

Wilson disease (WD) is a hereditary autosomal recessive disorder of copper metabolism, which results from mutations in the ATP7B gene. It is a monogenic disorder characterized by significant clinical heterogeneity in patients with renal, ocular, hepatic, and neurological involvement, complicating its clinical diagnosis. This study involves examination of an Iranian family with a child diagnosed with WD.

After various clinical tests, Whole Exome Sequencing (WES) and Sanger sequencing were carried out on the proband to identify the cause of the disease and verify the results. Segregation analysis was also performed. The next step was the study of protein conservation and its alterations after mutation.

The WES analysis revealed that the c.1883_1884del [p. His628ArgfsTer126] and c.2145 C > T variations in the ATP7B gene, in compound heterozygous form, were linked to WD in the proband. The analysis also determined that the proband inherited c.1883_1884del [p. His628ArgfsTer126] from his mother's side and c.2145 C > T from his father. A decrease in the amount of translated protein compared to the wild-type leads to the appearance of clinical symptoms in the affected individuals.

This study added criteria PP1, PP4 and PS4 to c.1883_1884del [p. His628ArgfsTer126] according to the ACMG guidelines and also supports a potential reclassification of c.2145 C > T variant from variant of uncertain significance (VUS) to likely pathogenic by adding PP4 and PM3. These findings will significantly help specialists in their decision-making about these variants.