Germline mutations in the new E1’ cryptic exon of the <i>VHL</i> gene in patients with tumours of von Hippel-Lindau disease spectrum or with paraganglioma

Buffet, Alexandre; Calsina, Bruna; Flores, Shahida K.; Giraud, Sophie; Lenglet, Marion; Romanet, Pauline; Deflorenne, Elisa; Aller, Javier; Bourdeau, Isabelle; Paillerets, Brigitte Bressac‐de; Calatayud, María; Dehais, Caroline; Pujol, Erwan de Monès del; Еленкова, Атанаска; Herman, Philippe; Kamenický, Peter; Lejeune, Sophie; Sadoul, J.L.; Barlier, Anne; Richard, Stéphane; Favier, Judith; Burnichon, Nelly; Gardie, Betty; Dahia, Patricia L.M.; Robledo, Mercedes; Gimenez-Roqueplo, A.-P.

doi:10.1136/jmedgenet-2019-106519

Cited by 16 publications

(15 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…This fact combined with the limited number of studies assessing vHL type 2C participants may have contributed to an overestimation of the frequency of PPGL in this subtype. Another limitation concerns the recently described germline mutations in the E1’ cryptic exon of the VHL gene in patients previously considered mutation negative, consisting of a small subset of patients possibly not assessed in the studies included in this meta-analysis ( 94 ). Another limitation concerns the lack of important information provided by primary studies, namely regarding sociodemographic data of the vHL participants and adequate characterization of PPGL when these occurred (i.e.…”

Section: Discussionmentioning

confidence: 99%

Pheochromocytomas and paragangliomas in von Hippel–Lindau disease: not a needle in a haystack

Castro-Teles

Sousa‐Pinto

Rebelo

et al. 2021

Endocrine Connections

View full text Add to dashboard Cite

Objective: Pheochromocytomas are a hallmark feature of von Hippel-Lindau disease (vHL). To our knowledge, this is the first systematic review with meta-analysis evaluating the frequency of pheochromocytomas and/or paragangliomas (PPGL) in patients with vHL, as well as among patients with different vHL subtypes. Design: Systematic review with meta-analysis. Methods: We searched on MEDLINE, Scopus and Web of Science. We included primary studies assessing participants with vHL and reporting on the frequency of PPGL. We performed random-effects meta-analysis to quantitatively assess the frequency of PPGL, followed by meta-regression and subgroup analysis. Risk of bias analysis was performed to assess primary studies’ methodological quality. Results: We included 80 primary studies. In 4263 patients with vHL, the pooled frequency of PPGL was 19.4% (95% confidence interval (CI)=15.9-23.6%, I²=86.1%). The frequency increased to 60.0% in patients with vHL type 2 (95%CI=53.4-66.3%, I²=54.6%) and was determined to be of 58.2% in patients with vHL type 2A (95%CI=49.7-66.3%, I²=36.2%), compared to 49.8% in vHL type 2B (95%CI=39.9-59.7%, I²=42.7%), and 84.1% in vHL type 2C (95%CI=75.1-93.1%, I²=0%). In meta-regression analysis, more recent studies were associated with a higher frequency of PPGL. All studies had at least one internal validity item classified as 'high risk of bias', with 13% studies having low risk of bias in all external validity items. Conclusions: PPGL are a common manifestation of vHL. Despite methodological limitations and differences across primary studies, our results point to the importance of PPGL screening in patients with vHL.

show abstract

Section: Discussionmentioning

confidence: 99%

Pheochromocytomas and paragangliomas in von Hippel–Lindau disease: not a needle in a haystack

Castro-Teles

Sousa‐Pinto

Rebelo

et al. 2021

Endocrine Connections

View full text Add to dashboard Cite

show abstract

“…This has previously been observed in patients with VHL from two separate studies in which a germline mutation was identified within the intron 1 of the VHL gene that created a cryptic exon. 17 18 This cryptic exon (termed E1’) dysregulated VHL splicing and resulted in loss of protein expression and the germline mutation would not have been detected by standard genetic testing. 17 18 Whereas, an example of the second scenario would be mutation of the TCEB1 gene which is another component of the VHL E3 ligase complex and has been reported as a potential mimic for VHL loss in sporadic ccRCC.…”

Section: Discussionmentioning

confidence: 99%

“… 17 18 This cryptic exon (termed E1’) dysregulated VHL splicing and resulted in loss of protein expression and the germline mutation would not have been detected by standard genetic testing. 17 18 Whereas, an example of the second scenario would be mutation of the TCEB1 gene which is another component of the VHL E3 ligase complex and has been reported as a potential mimic for VHL loss in sporadic ccRCC. 19 20 This report identifies a germline translocation that disrupts the VHL gene as a novel mechanism of gene loss in VHL that would not be detected by standard genetic testing.…”

Section: Discussionmentioning

confidence: 99%

A germline 1;3 translocation disrupting the VHL gene: a novel genetic cause for von Hippel-Lindau

et al. 2020

View full text Add to dashboard Cite

Von Hippel-Lindau (VHL) disease is an autosomal dominant hereditary tumour susceptibility disease caused by germline pathogenic variation of the VHL tumour suppressor gene. Affected individuals are at risk of developing multiple malignant and benign tumours in a number of organs.In this report, a male patient in his 20s who presented to the Urologic Oncology Branch at the National Cancer Institute with a clinical diagnosis of VHL was found to have multiple cerebellar haemangioblastomas, bilateral epididymal cysts, multiple pancreatic cysts, and multiple, bilateral renal tumours and cysts. The patient had no family history of VHL and was negative for germline VHL mutation by standard genetic testing. Further genetic analysis demonstrated a germline balanced translocation between chromosomes 1 and 3, t(1;3)(p36.3;p25) with a breakpoint on chromosome 3 within the second intron of the VHL gene. This created a pathogenic germline alteration in VHL by a novel mechanism that was not detectable by standard genetic testing.Karyotype analysis is not commonly performed in existing genetic screening protocols for patients with VHL. Based on this case, protocols should be updated to include karyotype analysis in patients who are clinically diagnosed with VHL but demonstrate no detectable mutation by existing genetic testing.

show abstract

“…Buffet et al studied the incidence of germline mutations in the cryptic exon (E1′) of VHL gene in patients with VHL disease, and in patients with PCC or PGL. They demonstrated that E′ VHL variants are rare, but nearly as frequent as the VHL variants in exons 1 and 2 in patients with PCC or PGL [ 174 ]. Hergovich et al discovered that VHL—specifically cytosolic VHL30—interacts with microtubules in vivo, and that amino acid residues 95–123 are necessary for microtubule stabilization and binding [ 98 ].…”

Section: Clinical and Genetic Features Of Selected Manifestations Of ...mentioning

confidence: 99%

The Role of VHL in the Development of von Hippel-Lindau Disease and Erythrocytosis

Hudler

Urbančič

2022

Genes

View full text Add to dashboard Cite

Von Hippel-Lindau disease (VHL disease or VHL syndrome) is a familial multisystem neoplastic syndrome stemming from germline disease-associated variants of the VHL tumor suppressor gene on chromosome 3. VHL is involved, through the EPO-VHL-HIF signaling axis, in oxygen sensing and adaptive response to hypoxia, as well as in numerous HIF-independent pathways. The diverse roles of VHL confirm its implication in several crucial cellular processes. VHL variations have been associated with the development of VHL disease and erythrocytosis. The association between genotypes and phenotypes still remains ambiguous for the majority of mutations. It appears that there is a distinction between erythrocytosis-causing VHL variations and VHL variations causing VHL disease with tumor development. Understanding the pathogenic effects of VHL variants might better predict the prognosis and optimize management of the patient.

show abstract

Germline mutations in the new E1’ cryptic exon of the VHL gene in patients with tumours of von Hippel-Lindau disease spectrum or with paraganglioma

Cited by 16 publications

References 27 publications

Pheochromocytomas and paragangliomas in von Hippel–Lindau disease: not a needle in a haystack

Pheochromocytomas and paragangliomas in von Hippel–Lindau disease: not a needle in a haystack

A germline 1;3 translocation disrupting the VHL gene: a novel genetic cause for von Hippel-Lindau

The Role of VHL in the Development of von Hippel-Lindau Disease and Erythrocytosis

Contact Info

Product

Resources

About