1Department of Medicine I, Medical University of Innsbruck, Innsbruck, Austria.
2VASCage Research Center on Vascular Ageing and Stroke, Innsbruck, Austria.
3Department of Neurology, Medical University of Innsbruck, Innsbruck, Austria.
4Department of Medical Genetics and Molecular Biology, University Hospital Lozenetz, Sofia, Bulgaria.
5Cambridge Liver Unit, Cambridge University Hospitals National Health Service (NHS) Foundation Trust, Cambridge, UK.
6Helios Klinikum Emil von Behring GmbH, Klinik für Innere Medizin II, Berlin, Germany.
7Department of Neuropediatrics, Charité University Medical Center Berlin, Berlin, Germany.
8Department of Surgery, Charité University Medical Center Berlin, Berlin, Germany.
9Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University Vienna, Vienna, Austria.
10Institute of Liver Studies, King's College Hospital NHS Foundation Trust, London, UK.
11Division of Pediatric Pulmology, Allergology, and Endocrinology, Department of Pediatrics and Adolescent Medicine, Comprehensive Center for Pediatrics, Medical University of Vienna, Vienna, Austria.
12Division of Gastroenterology and Hepatology, Department of Internal Medicine, Medical University of Graz, Graz, Austria.
13Christian Doppler Laboratory on Iron and Phosphate Biology, Innsbruck, Austria.
14Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland.
15Department of Pediatrics I, Medical University of Innsbruck, Innsbruck, Austria.
16Ludwig Boltzmann Institute for Rare and Undiagnosed Diseases, Vienna, Austria.
17Department of Pediatrics and Adolescent Medicine, Medical University of Vienna, Vienna, Austria.
18St. Anna Children's Cancer Research Institute, Vienna, Austria.
19Internal Medicine, Krankenhaus Salem der Evangelischen Stadtmission, Heidelberg, Germany.
20University of Washington School of Medicine, Seattle Children's Hospital, Seattle, Washington, USA.
Wilson disease (WD) is caused by biallelic pathogenic variants in adenosine triphosphatase copper-transporting beta (ATP7B); however, genetic testing identifies only one or no pathogenic ATP7B variant in a number of patients with WD. Synonymous single-nucleotide sequence variants have been recognized as pathogenic in individual families. The aim of the present study was to evaluate the prevalence and disease mechanism of the synonymous variant c.2292C>T (p.Phe764=) in WD. A cohort of 280 patients with WD heterozygous for a single ATP7B variant was investigated for the presence of c.2292C>T (p.Phe764=). In this cohort of otherwise genetically unexplained WD, the allele frequency of c.2292C>T (p.Phe764=) was 2.5% (14 of 560) compared to 7.1 × 10-6 in the general population (2 of 280,964 in the Genome Aggregation Database; p < 10-5; Fisher exact test). In an independent United Kingdom (UK) cohort, 2 patients with WD homozygous for p.Phe764= were identified. RNA analysis of ATP7B transcripts from patients homozygous or heterozygous for c.2292C>T and control fibroblasts showed that this variant caused high expression of an ATP7B transcript variant lacking exon 8. Conclusion: The synonymous ATP7B variant c.2292C>T (p.Phe764=) causes abnormal messenger RNA processing of ATP7B transcripts and is associated with WD in compound heterozygotes and homozygotes.