Analyses of ATP7B mRNA in Nasopharyngeal Swab Samples Increase Yields of Wilson Disease Molecular Genetic Diagnostics - Nasopharyngeal swab collection; Visualization of in silico HSF predictions and ATP7B Exon 8 skipping

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Wilson disease (WD) is an autosomal recessive disorder of copper transport caused by bi-allelic pathogenic variants in the ATPasecopper transporting beta gene (ATP7B). Results of standard genetic diagnostics remain inconclusive in 3%–20% of WD patients inpart due to problematic assessment of variants of unknown or conflicting pathogenicity (synonymous variants included). Correctinterpretation of potential effects of such variants can be substantially enhanced by RNA analyses. This strategy is, however, oflimited utility in WD patients because of predominant liver expression of ATP7B. To avoid invasive bioptic liver collection andincrease WD diagnostic yields, we searched for a surrogate tissue sample and identified profiles of ATP7B transcripts innasopharyngeal swabs that were comparable to liver. Amplicons spanning ATP7B Exons 3–21 were prepared from the swabWileyHuman MutationVolume 2026, Article ID 8416660, 12 pageshttps://doi.org/10.1155/humu/8416660material and analysed by long-read nanopore sequencing to enable the detection of splicing changes and variant phasing.Diagnostic utility of this novel in vivo methodology was demonstrated by characterization of mRNA splicing abnormalitiescaused by synonymous ATP7B variants c.1488C>T (p.(Gly496=)), c.2241C>T (p.(Ile747=)), c.2292C>T (p.(Phe764=)), and anonsense variant c.2336G>A (p.(Trp779Ter)) in four WD patients, who were not genetically resolved by standard techniques.Nasopharyngeal swab sampling is minimally invasive and allows effective analyses of mRNA to detect and/or validate effects ofATP7B variants in WD patients. Conclusive genetic diagnosis attained by this novel technique may facilitate family counsellingand substantiate initiation of copper-chelation therapy in presymptomatic individuals. Data Availability Statement The data that support the findings of this study are availableon request from the corresponding author. The data are notpublicly available due to privacy or ethical restrictions.

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