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ATP7B variant spectrum in a French pediatric Wilson disease cohort

Eduardo Couchonnal1, Sophie Bouchard2, Thomas Damgaard Sandahl3

  • 1Hospices Civils de Lyon. National Center for Wilson's Disease and Department of Pediatric Gastroenterology, Hepatology and Nutrition Children's Hospital of Lyon, France; European Reference Network on Hepatological Diseases (ERN RARE-LIVER), Germany.

European Journal of Medical Genetics
|August 17, 2021
PubMed

Insights

The most common ATP7B variant in France is p.His1069Gln. Nonsense/frameshift variants in Wilson disease patients are linked to lower ceruloplasmin levels, indicating genotype-phenotype correlations.

Area of Science:

  • Genetics
  • Molecular Biology
  • Biochemistry

Background:

  • The geographical distribution of ATP7B variants, crucial for Wilson disease diagnosis, is not well-documented in the French population.
  • Wilson disease (WD) is an autosomal recessive disorder caused by mutations in the ATP7B gene, leading to copper accumulation.

Purpose of the Study:

  • To characterize the spectrum of ATP7B variants in a cohort of French pediatric Wilson disease patients.
  • To identify the most prevalent ATP7B variants and their distribution within the French population.
  • To explore genotype-phenotype correlations, specifically the relationship between variant types and ceruloplasmin levels.

Main Methods:

  • A retrospective analysis of clinical and genetic data from 113 children diagnosed with Wilson disease in France between 1995 and 2020.
  • Epidemiological, clinical, laboratory, and genetic data were collected from the French national WD registry.
  • Variant analysis included identification of novel variants, recurrent mutations, variant types (truncating, missense), and exon distribution.

Main Results:

  • The study identified 102 distinct ATP7B variants, including 14 novel ones, in 113 French pediatric patients.
  • The p.His1069Gln variant was the most frequent, found in 14.2% of alleles, with only seven homozygous cases.
  • Hepatic manifestations were predominant at diagnosis (79.8%), while 15.8% presented with neurological symptoms. Patients with two nonsense/frameshift variants had significantly lower ceruloplasmin levels compared to those with two missense variants (2.8 vs. 8.4 mg/dl).

Conclusions:

  • The p.His1069Gln variant is the most common in the French pediatric Wilson disease population, with significant heterogeneity observed for other ATP7B variants.
  • Exons 14, 8, and 3 of the ATP7B gene are the most frequently mutated.
  • Nonsense/frameshift variants are associated with lower ceruloplasmin levels, suggesting a correlation between variant type and disease severity.
Abstract

Keywords:
ATP7BPhenotype-genotype correlationWilson's diseasep.His1069Gln

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