Investigation of germline VHL variants in Iranian patients with retinal capillary hemangioblastoma and genotype-phenotype analysis

ABSTRACT

Background

Retinal capillary hemangioblastoma (RCH), while sporadic in some cases, is the most common and earliest manifestation of von Hippel-Lindau disease (VHL). This is the first report on different types of VHL variants and genotype-phenotype correlations in Iranian families with RCH.

Materials and methods

In this prospective observational case series study, 17 families with RCH were included. PCR was performed to amplify 3 exons of VHL gene. Afterward, Sanger sequencing was performed on all PCR products. For the detection of VHL copy number variations, MLPA was used.

Results

Our study identified 10 different types of VHL variants. Missense mutations were the most common variants found and affected the structure of α domain of the VHL protein (pVHL). The majority of mutations (72.7%) in the patients with RCH and central nervous system hemangioblastoma (CNS-HB) were located on α domain.

Conclusion

α domain of VHL may play a potential role in the pathogenesis of RCH. Our findings suggest that genotype-phenotype characteristics in those variants in α- domain may predispose patients to RCH with CNS-HB.

KEYWORDS:

• VHL
• RCH
• Iranian patients

List of abbreviations

(RCH)	=	Retinal capillary hemangioblastoma
(VHL)	=	von Hippel-Lindau disease
(pVHL)	=	VHL protein
(CNS-HB)	=	Central nervous system hemangioblastoma
(RCC)	=	Cclear cell renal carcinoma
(ELST)	=	Endolymphatic sac tumor
(PCC)	=	Pheochromocytomas
(PC)	=	Pancreatic
(KC)	=	Kidney cysts
(HIF)	=	Hypoxia-inducible factors
(VEGF)	=	Vascular endothelial growth factor
(PDGF)	=	Platelet-derived growth factor
(CCT)	=	Chaperonin-containing tailless complex polypeptide 1

Disclosure statement

The authors report no conflicts of interest. The authors alone are responsible for the content and writing of this article.

Author’s contributions

M.N. designed the study and finalized the manuscript; F.A. wrote the main manuscript text, performed genetic analysis, genetic tests and interpretation of data; S.T. designed the study and assisted in the genetic analyses; A.S. designed the study; R.M. commented on and revised the manuscript; R.K. collected samples; Z.A. performed genetic tests; G.KH. Supervised the study and commented on the manuscript. All authors read and approved the final version.

Code availability

Ethics code: IR.IUMS.REC.1399.109

Consent for publication

All authors and patients

Consent to participate

Informed consent was obtained from the parents or guardians of all patients who participated in the study.

Availability of data and materials

All datasets generated for this study are included in the article.

Additional information

Funding

This work supported by grant form research deputy of eye research center, Tehran, Iran.