ORIGINAL RESEARCH article
Front. Genet.
Sec. Statistical Genetics and Methodology
Volume 16 - 2025 | doi: 10.3389/fgene.2025.1604683
This article is part of the Research TopicFunctional Study of Novel VUS (Variant of Uncertain Significance) Mutations in Single-gene Inherited Disease, Volume IIView all 3 articles
Silent but Significant: Functional Elucidation of a Synonymous ATP7B Mutation in Wilson's Disease Pedigrees
Provisionally accepted
- 1Jinzhou Medical University graduate training base, Suizhou Central Hospital affiliated to Hubei University of Medicine, Suizhou, China
- 2Xiangyang Integrated Traditional Chinese and Western Medicine Hospital, Xiangyang, China
- 3Respiratory endoscopy center，Suizhou Central Hospital, Hubei University of Medicine, Suizhou, China
- 4Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, China
- 5Department of Laboratory, Suizhou Central Hospital, Hubei University of Medicine, Suizhou, China
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Wilson's disease (hepatolenticular degeneration) was a common hereditary neurological disorder. Early diagnosis, particularly the widespread implementation of genetic testing and timely intervention, is crucial for improving the prognosis of this disease. However, limited data exists on genotype-phenotype correlations, thereby impeding accurate early clinical diagnosis. This study performed whole-exome sequencing on the proband and family members to detect genetic variants, identifying a synonymous mutation (ATP7B c.2145C>T, p. Tyr715=) clinically associated with the phenotype and a pathogenic frameshift mutation (c.2304dupC, p. Met769Hisfs*26) in the proband. Bioinformatics tools (HSF, SpliceAI, ESE Finder 3.0) predicted that the c.2145C>T mutation might disrupt nearby splicing sites. In vitro minigene assays confirmed aberrant precursor mRNA splicing caused by this synonymous mutation, resulting in reduced abundance of normal transcripts. The frameshift mutation c.2304dupC (p. Met769His fs*26) on the other allele was a known pathogenic variant causing protein truncation. The compound heterozygous variants (c.2145C>T and c.2304dupC) in ATP7B likely synergistically contribute to the proband's abnormal clinical phenotype, aligning with the recessive inheritance pattern of Wilson disease.
Keywords: degeneration, ATP7B gene, synonymous mutation, Sanger sequencing, minigene assay
Received: 02 Apr 2025; Accepted: 02 May 2025.
Copyright: © 2025 Zhang, Xie, Li and Huang. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
* Correspondence:
Yulei Li, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, China
Hongyao Huang, Jinzhou Medical University graduate training base, Suizhou Central Hospital affiliated to Hubei University of Medicine, Suizhou, China
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