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

Alexandre Buffet, Bruna Calsina, Shahida Flores, Sophie Giraud, Marion Lenglet, Pauline Romanet, Elisa Deflorenne, Javier Aller, Isabelle Bourdeau, Brigitte Bressac-De Paillerets, María Calatayud, Caroline Dehais, Erwan De Mones Del Pujol, Atanaska Elenkova, Philippe Herman, Peter Kamenický, Sophie Lejeune, Jean Louis Sadoul, Anne Barlier, Stephane RichardJudith Favier, Nelly Burnichon, Betty Gardie, Patricia L. Dahia, Mercedes Robledo, Anne Paule Gimenez-Roqueplo

Research output: Contribution to journalArticlepeer-review

7 Scopus citations


Backgrounds The incidence of germline mutations in the newly discovered cryptic exon (E1') of VHL gene in patients with von Hippel-Lindau (VHL) disease and in patients with paraganglioma or pheochromocytoma (PPGL) is not currently known. Methods We studied a large international multicentre cohort of 1167 patients with a previous negative genetic testing. Germline DNA from 75 patients with a single tumour of the VHL spectrum (Single VHL tumour cohort), 70 patients with multiple tumours of the VHL spectrum (Multiple VHL tumours cohort), 76 patients with a VHL disease as described in the literature (â € VHL-like' cohort) and 946 patients with a PPGL were screened for E1' genetic variants. Results Six different genetic variants in E1' were detected in 12 patients. Two were classified as pathogenic, 3 as variants of unknown significance and 1 as benign. The rs139622356 was found in seven unrelated patients but described in only 16 patients out of the 31 390 of the Genome Aggregation Database (p<0.0001) suggesting that this variant might be either a recurrent mutation or a modifier mutation conferring a risk for the development of tumours and cancers of the VHL spectrum. Conclusions VHL E1 cryptic exon mutations contribute to 1.32% (1/76) of VHL-like cohort and to 0.11% (1/946) of PPGL cohort and should be screened in patients with clinical suspicion of VHL, and added to panels for Next Generation Sequencing (NGS) diagnostic testing of hereditary PPGL. Our data highlight the importance of studying variants identified in deep intronic sequences, which would have been missed by examining only coding sequences of genes/exomes. These variants will likely be more frequently detected and studied with the upcoming implementation of whole-genome sequencing into clinical practice.

Original languageEnglish (US)
Pages (from-to)752-759
Number of pages8
JournalJournal of medical genetics
Issue number11
StatePublished - Nov 1 2020


  • cryptic exon
  • paraganglioma
  • von Hippel-Lindau

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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