The spectrum of pathogenic variants of the ATP7B gene in Wilson disease in the Russian Federation.
BACKGROUND
Wilson's disease (WD) is a rare inherited disorder caused by mutations in the ATP7B gene resulting in copper accumulation in different organs. However, data on ATP7B mutation spectrum in Russia and worldwide are insufficient and contradictory. The objective of the present study was estimation of the frequency of ATP7B gene mutations in the Russian population of WD patients.


MATERIALS AND METHODS
75 WDpatients were examined by next-generation sequencing (NGS). A targeted panel NimbleGen SeqCap EZ Choice: 151012_HG38_CysFib_EZ_HX3 (ROCHE)was designed for analysis of ATP7B gene and possible modifier genes. Retrospective assessment of a diagnostic WD score (Leipzig, 2001) was also performed.


RESULTS
31 mutations in ATP7B gene were detected. Two most frequent mutations were c.3207C > A (51,85% of alleles) and c.3190 G > A (8,64% of alleles). Single rare mutations were detected in 29% of cases. In 96% cases mutations of both copies of the ATP7B were revealed. We also observed 3 novel potentially pathogenic variants which were not previously described (c.1870-8A > G, c.3655A > T (p.Ile1219Phe), c.3036dupC (p.Lys1013fs). For 25% of patients at the time of the manifestation the diagnosis WD could not be established using the earlier proposed diagnostic score. There was a remarkable delay in diagnosis for the majority of patients. Only 33% of patients WD was diagnosed in three months after the first symptoms, 29%patients - in 3-12 months, 30% - in 1-10 years, in 8% - more than 10 years. Generally, clinical appearance of WD may be rather variable at manifestation and genetic profiling at this step is the only way to confirm the presence of WD.
['Balashova|Mariya S|MS|', 'Tuluzanovskaya|Inna G|IG|', 'Glotov|Oleg S|OS|', 'Glotov|Andrey S|AS|', 'Barbitoff|Yury A|YA|', 'Fedyakov|Mikhail A|MA|', 'Alaverdian|Diana A|DA|', 'Ivashchenko|Tatiana E|TE|', 'Romanova|Olga V|OV|', 'Sarana|Andrey M|AM|', 'Scherbak|Sergey G|SG|', 'Baranov|Vladislav S|VS|', 'Filimonov|Marat I|MI|', 'Skalny|Anatoly V|AV|', 'Zhuchenko|Natalya A|NA|', 'Ignatova|Tatiana M|TM|', 'Asanov|Aliy Y|AY|']
D000328:Adult D000073840:Copper-Transporting ATPases D005260:Female D020869:Gene Expression Profiling D014644:Genetic Variation D006527:Hepatolenticular Degeneration D059014:High-Throughput Nucleotide Sequencing D006801:Humans D008297:Male D009154:Mutation D016133:Polymerase Chain Reaction D012426:Russia
ATP7B Wilson's disease NGS Targeted panel Degeneration Hepatocerebellar