Low penetrance of frequent ATP7B mutations explains the low prevalence of Wilson disease. Lessons from real-life registries.
Genetic screening
Genotype-phenotype correlation
Misdiagnosis
Rare liver disease
Journal
Digestive and liver disease : official journal of the Italian Society of Gastroenterology and the Italian Association for the Study of the Liver
ISSN: 1878-3562
Titre abrégé: Dig Liver Dis
Pays: Netherlands
ID NLM: 100958385
Informations de publication
Date de publication:
24 Sep 2024
24 Sep 2024
Historique:
received:
09
05
2024
revised:
03
08
2024
accepted:
03
09
2024
medline:
26
9
2024
pubmed:
26
9
2024
entrez:
25
9
2024
Statut:
aheadofprint
Résumé
Wilson disease (WD) is a copper metabolism disorder caused by mutations in ATP7B gene, with significant clinical variability. Several studies have analyzed the prevalence and penetrance of mutations. We evaluated both characteristics for our more frequent mutations. Evaluation of 260 patients from the National Registry: clinical, analytical and genetic data. Estimation of homozygotes and total cases according to Hardy-Weinberg equilibrium and comparison with Registry records. The estimated number of homozygotes were higher than registered: p.Met645Arg (1949/6), p.His1069Gln (20/8), p.Leu708Pro (63/24) and p.Gly869Arg (147/0). p.Met645Arg homozygotes presented less cirrhosis at diagnosis, extrahepatic disease and Kayser-Fleischer ring (KFR) and more presymptomatic cases and diagnosis after 40 years of age than p.Leu708Pro and p.His1069Gln homozygotes. p.Met645Arg homozygotes presented more late diagnosis than p.Met645Arg compound heterozygotes. Compound heterozygotes carrying p.Met645Arg or p.Gly869Arg showed less cirrhosis at diagnosis, KFR and neurological symptoms and more hepatic and presymptomatic cases, despite clearly low ceruloplasmin levels. The estimated prevalence was 1:3.785, predicting more than 10.500 patients. The widespread mutations p.Met645Arg and p.Gly869Arg show low penetrance. WD might be underdiagnosed in Spain due to less severe phenotype of the most frequent mutations, a crucial fact to avoid misdiagnosis and to offer early therapy.
Sections du résumé
BACKGROUND & AIMS
OBJECTIVE
Wilson disease (WD) is a copper metabolism disorder caused by mutations in ATP7B gene, with significant clinical variability. Several studies have analyzed the prevalence and penetrance of mutations. We evaluated both characteristics for our more frequent mutations.
METHODS
METHODS
Evaluation of 260 patients from the National Registry: clinical, analytical and genetic data. Estimation of homozygotes and total cases according to Hardy-Weinberg equilibrium and comparison with Registry records.
RESULTS
RESULTS
The estimated number of homozygotes were higher than registered: p.Met645Arg (1949/6), p.His1069Gln (20/8), p.Leu708Pro (63/24) and p.Gly869Arg (147/0). p.Met645Arg homozygotes presented less cirrhosis at diagnosis, extrahepatic disease and Kayser-Fleischer ring (KFR) and more presymptomatic cases and diagnosis after 40 years of age than p.Leu708Pro and p.His1069Gln homozygotes. p.Met645Arg homozygotes presented more late diagnosis than p.Met645Arg compound heterozygotes. Compound heterozygotes carrying p.Met645Arg or p.Gly869Arg showed less cirrhosis at diagnosis, KFR and neurological symptoms and more hepatic and presymptomatic cases, despite clearly low ceruloplasmin levels. The estimated prevalence was 1:3.785, predicting more than 10.500 patients.
CONCLUSIONS
CONCLUSIONS
The widespread mutations p.Met645Arg and p.Gly869Arg show low penetrance. WD might be underdiagnosed in Spain due to less severe phenotype of the most frequent mutations, a crucial fact to avoid misdiagnosis and to offer early therapy.
Identifiants
pubmed: 39322449
pii: S1590-8658(24)01000-4
doi: 10.1016/j.dld.2024.09.002
pii:
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Informations de copyright
Copyright © 2024 Editrice Gastroenterologica Italiana S.r.l. Published by Elsevier Ltd. All rights reserved.
Déclaration de conflit d'intérêts
Conflict of interest Victor Vargas: Speaker fees, Alexion Pharma, Consultant (advisory board), Ipsen. Anna Miralpeix: speaker fees from Orphalan. Zoe Mariño: speaker fees from Orphalan and Gilead; advisory fees from Orphalan, Alexion and Deep Genomics; grants from Gilead. The others authors reported no conflict of interest.