TY - JOUR T1 - Germline mutations in the new E1’ cryptic exon of the <em>VHL</em> gene in patients with tumours of von Hippel-Lindau disease spectrum or with paraganglioma JF - Journal of Medical Genetics JO - J Med Genet SP - 752 LP - 759 DO - 10.1136/jmedgenet-2019-106519 VL - 57 IS - 11 AU - Alexandre Buffet AU - Bruna Calsina AU - Shahida Flores AU - Sophie Giraud AU - Marion Lenglet AU - Pauline Romanet AU - Elisa Deflorenne AU - Javier Aller AU - Isabelle Bourdeau AU - Brigitte Bressac-de Paillerets AU - María Calatayud AU - Caroline Dehais AU - Erwan De Mones Del Pujol AU - Atanaska Elenkova AU - Philippe Herman AU - Peter Kamenický AU - Sophie Lejeune AU - Jean Louis Sadoul AU - Anne Barlier AU - Stephane Richard AU - Judith Favier AU - Nelly Burnichon AU - Betty Gardie AU - Patricia L Dahia AU - Mercedes Robledo AU - Anne-Paule Gimenez-Roqueplo Y1 - 2020/11/01 UR - http://jmg.bmj.com/content/57/11/752.abstract N2 - 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&lt;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. ER -