The spectrum of pathogenic variants of the ATP7B gene in Wilson disease in the Russian Federation.
ATP7B
Degeneration
Hepatocerebellar
NGS
Targeted panel
Wilson's disease
Journal
Journal of trace elements in medicine and biology : organ of the Society for Minerals and Trace Elements (GMS)
ISSN: 1878-3252
Titre abrégé: J Trace Elem Med Biol
Pays: Germany
ID NLM: 9508274
Informations de publication
Date de publication:
May 2020
May 2020
Historique:
received:
09
06
2019
revised:
21
10
2019
accepted:
22
10
2019
pubmed:
12
11
2019
medline:
29
12
2020
entrez:
12
11
2019
Statut:
ppublish
Résumé
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. 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. 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.
Sections du résumé
BACKGROUND
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
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
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.
Identifiants
pubmed: 31708252
pii: S0946-672X(19)30380-3
doi: 10.1016/j.jtemb.2019.126420
pii:
doi:
Substances chimiques
ATP7B protein, human
EC 7.2.2.8
Copper-Transporting ATPases
EC 7.2.2.8
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
126420Informations de copyright
Copyright © 2019. Published by Elsevier GmbH.