Molecular-genetic diagnostics of von Hippel-Lindau syndrome (VHL) in Bulgaria: first complex mutation event in the VHL gene

ABSTRACT

Von Hippel-Lindau syndrome is an autosomal-dominant disease characterized by the formation of various tumours and cysts in many different parts of the body. Von Hippel-Lindau syndrome is caused by VHL gene mutations leading to production of impaired tumor suppressor Von Hippel-Lindau syndrome protein or its complete absence. Purpose: To study five patients with clinically suspected Von Hippel-Lindau syndrome, who were referred for molecular genetic testing. Methods: Sanger sequencing of the coding regions of the VHL gene. Results: Five clinically relevant germline mutations were detected. One of the pathogenic variants has not been previously reported. This novel mutation is a complex mutation event combining a duplication and an indel, rearranging exon 3 of the VHL gene - c. [516_517dupGTCAAGCCT; 532_542delCTGGACATCGTinsATTA], p. (Glu173Serfs*4). Conclusion: Overall, our results showed that the diagnosis of Von Hippel-Lindau syndrome in our country is difficult most probably because of its heterogeneous clinical manifestation and insufficient knowledge on the diagnostic criteria for the disease. From genetic point of view our results add some novel data on the mutation profile of the VHL gene. In order to prove or revise the diagnosis, early genetic testing is strongly recommended in affected patients and their family members to ensure appropriate follow-up and treatment of the malignancies.

KEYWORDS:

• VHL
• VHL gene
• haemangioblastoma
• complex mutation event

Acknowledgments

The authors thank the physicians for the clinical description of the cases. We are grateful to the patients and their families for their cooperation.

Disclosure statement

The authors declare that they have no conflict of interest.

Ethical approval

The work was approved by the Ethics Committee of Sofia Medical University.

Informed consent

Informed consent was obtained from all individual participants included in the study.

Additional information

Funding

The study was funded by the Medical University Sofia, Bulgaria [grant number 1-D/2016].

Notes on contributors

Maria Glushkova

Maria Glushkova is a PhD student at Department of Chemistry and Biochemistry and principle investigator on research project in the Genetic Medico-Diagnostic Laboratory “Genica”.

Petia Dimova

Petia Dimova is a neurologist and neurosurgeon at Department of Neurosurgery in the University Hospital “St. Ivan Rilski”.

Iglika Yordanova

Iglika Yordanova is a PhD and senior researcher in Genetic Medico-Diagnostic Laboratory “Genica”.

Tihomir Todorov

Tihomir Todorov is a PhD and senior researcher in Genetic Medico-Diagnostic Laboratory “Genica”.

Ivan Tourtourikov

Ivan Tourtourikov is a student preparing his MSc thesis in Genetic Medico-Diagnostic Laboratory “Genica”.

Vanyo Mitev

Vanyo Mitev is an academic and head of the Department of Medical Chemistry and Biochemistry, Medical University Sofia.

Albena Todorova

Albena Todorova is a professor at Department of Medical Chemistry and Biochemistry, Medical University Sofia. She is a director of the Genetic Medico-Diagnostic Laboratory “Genica”.