Wilson-Konovalov disease in pediatric practice: molecular genetic features, relationships between genotype and phenotype

Objective. To determine the spectrum and relative frequencies of pathogenic variants of the ATP7B gene and to study the relationships between the genotype and phenotype of the disease in Russian children with Wilson-Konovalov disease.
Methods. The study included 100 children (3-17 years old) with a genetically verified diagnosis of fibroid tumor, observed in the period 2012-2023, who underwent a comprehensive examination: the level of ceruloplasmin in the blood and daily excretion of copper in the urine were determined, magnetic resonance imaging of the brain, ophthalmological examination using a slit lamp, indirect fibroelastometry (the degree of fibrosis was assessed using the METAVIR scale). A search for specific variants of the ATP7B gene was performed using real-time PCR, Sanger sequencing, and high-throughput sequencing (HTS).
Results. 51 pathogenic variants of ATP7B were detected, including 14 previously unknown. The most common variants were c.3207C>A, detected on 45.5% of alleles, c.3402del – 6.5%, c.3190G>A – 6%, and c.2304insC – 5.5%. The presence of the major c.3207C>A genotype is associated with late onset and mild liver damage, while the presence of variants leading to premature translation termination are associated with early onset, severe liver damage, and lower ceruloplasmin levels (p < 0.001). The diagnostic efficacy of the standard PCR panel, assessed by the detection of two pathogenic variants, was only 39%, while the high-throughput sequencing allowed the identification of biallelic variants in 99% of patients.
Conclusion. A unique spectrum of ATP7B gene variants with pronounced genetic heterogeneity has been identified in the Russian children with WKD. The established relationships between WKD genotype and age of onset, the degree of liver damage, and ceruloplasmin levels offer potential for predicting the course of the disease and improving diagnostic algorithms.

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