A nonsense mutation in VHL causing Von Hippel-Lindau syndrome in a large Chinese family—a genetic study of familial neoplastic disease

Abstract

Von Hippel-Lindau (VHL) syndrome is a multi-organ neoplastic disease characterized by highly vascular and cystic tumors in the central nervous system (CNS), retina, and visceral lesions, which are mainly caused by germline mutations in VHL. We aimed to detect novel mutations in VHL gene in families with VHL. Here, a large consanguineous four-generation family with variant phenotypes of VHL syndrome was recruited, and its molecular genetics were tested via Sanger sequencing. And various tools and databases were used to predict the variant pathogenicity, frequency, and protein function. Genetic investigation detected a c.351G > A nonsense mutation in VHL that altered the downstream reading frame and created a premature TGA stop signal, resulting in severely truncated pVHL (p.Trp117Ter). This mutation is absent from most public databases, and functional prediction bioinformatic tools demonstrated that this residue is conserved and that this variant is highly likely to be deleterious. The c.315G > A nonsense mutation in VHL is the causal mutation of this kindred that may lead to clear familial aggregation of VHL syndrome because of the dysfunction of the truncated pVHL.

Keywords:

• VHL
• hemangioblastoma
• mutation
• genotype–phenotype correlation

Acknowledgments

The authors sincerely thank the family members who participated in this research. We thank Beijing Ditan Hospital Specimen Bank Project for specimen storage.

Authorship contribution statement

Conceptualization: DX, LT, FE and WT

Data curation: DX and LT

Formal Analysis: DX and FE

Funding acquisition: DX, LT and FE

Investigation: DX

Methodology: DX, LT and LB

Project administration: LT, FE and WT

Resources: LB, WF, WS, LB, ZX and CS

Software: DX

Supervision: FE and WT

Validation: LJ, LB and LT

Visualization: FE

Writing – original draft: DX

Writing – review & editing: LT, LB and FE

Disclosure statement

No potential conflict of interest was reported by the authors.

Additional information

Funding

Seedling plan of Beijing Ditan Hospital Research Fund (DTYM-202106) and Key laboratory open research of Beijing Ditan Hospital (DTKF-202203) and Beijing Municipal Administration of Hospitals Incubating Program (PX-2024065).