RT Journal Article SR Electronic T1 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 JF Journal of Medical Genetics JO J Med Genet FD BMJ Publishing Group Ltd SP 752 OP 759 DO 10.1136/jmedgenet-2019-106519 VO 57 IS 11 A1 Alexandre Buffet A1 Bruna Calsina A1 Shahida Flores A1 Sophie Giraud A1 Marion Lenglet A1 Pauline Romanet A1 Elisa Deflorenne A1 Javier Aller A1 Isabelle Bourdeau A1 Brigitte Bressac-de Paillerets A1 María Calatayud A1 Caroline Dehais A1 Erwan De Mones Del Pujol A1 Atanaska Elenkova A1 Philippe Herman A1 Peter Kamenický A1 Sophie Lejeune A1 Jean Louis Sadoul A1 Anne Barlier A1 Stephane Richard A1 Judith Favier A1 Nelly Burnichon A1 Betty Gardie A1 Patricia L Dahia A1 Mercedes Robledo A1 Anne-Paule Gimenez-Roqueplo YR 2020 UL http://jmg.bmj.com/content/57/11/752.abstract AB 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 (‘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.