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Abstract
Background/Objectives: Wilson’s disease (WD) is a rare genetic disorder of impaired copper metabolism due to pathogenic variants in the ATP7B. The diagnosis is based on the Leipzig criteria, clinical signs, laboratory features and genetic testing. This study aims to investigate additional genetic explanations for WD symptoms and abnormal laboratory tests in patients without a confirmed ATP7B genotype.
Methods: Ten patients with clinically confirmed WD and one or none pathogenic ATP7B gene variant underwent whole-genome sequencing. The ATP7B was analyzed for coding and non-coding and structural variants and, if no candidate variant was identified, coding variants in “Mendeliome” gene panel (n = 4296) was analyzed for an alternative molecular cause.
Results: Two patients had the most common pathogenic variant in the ATP7B, NM_000053.3:c.3207C>A p.(His1069Gln), in a heterozygous state, one of which carried also VUS in CP – NM_000096.4:c.1209-3C > A (PM2; PP3). Two patients were carriers of likely pathogenic variants in the CP gene: NM_000096.4:c.2527_2528del p.(Ser843PhefsTer10) (PVS1; PM2) and NM_000096.4:c.2426-1G > C (PVS1; PM2). Three patients with CP gene variants had lower ceruloplasmin levels (0.0993 ± 0.0269 mg/dl) than those without the variants (0.1567 ± 0.0172 mg/dl). Six individuals had no ATP7B variants and no additional candidate variants identified using WGS.
Conclusion. Low ceruloplasmin levels, a diagnostic criterion for WD, can be caused by various factors, including CP gene variants in a heterozygous state. It highlights the importance of reviewing diagnostic criteria for WD and shows that CP gene variants can mislead the WD diagnosis.
Methods: Ten patients with clinically confirmed WD and one or none pathogenic ATP7B gene variant underwent whole-genome sequencing. The ATP7B was analyzed for coding and non-coding and structural variants and, if no candidate variant was identified, coding variants in “Mendeliome” gene panel (n = 4296) was analyzed for an alternative molecular cause.
Results: Two patients had the most common pathogenic variant in the ATP7B, NM_000053.3:c.3207C>A p.(His1069Gln), in a heterozygous state, one of which carried also VUS in CP – NM_000096.4:c.1209-3C > A (PM2; PP3). Two patients were carriers of likely pathogenic variants in the CP gene: NM_000096.4:c.2527_2528del p.(Ser843PhefsTer10) (PVS1; PM2) and NM_000096.4:c.2426-1G > C (PVS1; PM2). Three patients with CP gene variants had lower ceruloplasmin levels (0.0993 ± 0.0269 mg/dl) than those without the variants (0.1567 ± 0.0172 mg/dl). Six individuals had no ATP7B variants and no additional candidate variants identified using WGS.
Conclusion. Low ceruloplasmin levels, a diagnostic criterion for WD, can be caused by various factors, including CP gene variants in a heterozygous state. It highlights the importance of reviewing diagnostic criteria for WD and shows that CP gene variants can mislead the WD diagnosis.
Original language | English |
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Article number | EP08.030 |
Pages (from-to) | 1029-1030 |
Number of pages | 2 |
Journal | European Journal of Human Genetics |
Volume | 32 |
Issue number | Suppl. 2 |
Publication status | Published - 6 Dec 2024 |
Event | 57th European Society of Human Genetics (ESHG) Conference - Berlin, Germany Duration: 1 Jun 2024 → 4 Jun 2024 Conference number: 57 https://www.nature.com/articles/s41431-024-01731-7 |
Keywords*
- Wilson disease
- ATP7B
Field of Science*
- 3.1 Basic medicine
Publication Type*
- 3.4. Other publications in conference proceedings (including local)
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EP08.030 Other possible genetic causes of low ceruloplasmin levels in patients with clinically suspected Wilson’s disease
Zariņa, A. (Speaker), Gailīte, L. (Co-author), Puzuka, A. (Co-author), Auzenbaha, M. (Co-author), Tolmane, I. (Co-author), Krūmiņa, Z. (Co-author), Gailīte, L. (Co-author) & Rots, D. (Co-author)
1 Jun 2024 → 4 Jun 2024Activity: Talk or presentation types › Poster presentation