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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

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...

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Autores principales: Buffet, Alexandre, Calsina, Bruna, Flores, Shahida, Giraud, Sophie, Lenglet, Marion, Romanet, Pauline, Deflorenne, Elisa, Aller, Javier, Bourdeau, Isabelle, Bressac-de Paillerets, Brigitte, Calatayud, María, Dehais, Caroline, De Mones Del Pujol, Erwan, Elenkova, Atanaska, Herman, Philippe, Kamenický, Peter, Lejeune, Sophie, Sadoul, Jean Louis, Barlier, Anne, Richard, Stephane, Favier, Judith, Burnichon, Nelly, Gardie, Betty, Dahia, Patricia L, Robledo, Mercedes, Gimenez-Roqueplo, Anne-Paule
Formato: Online Artículo Texto
Lenguaje:English
Publicado: BMJ Publishing Group 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387210/
https://www.ncbi.nlm.nih.gov/pubmed/31996412
http://dx.doi.org/10.1136/jmedgenet-2019-106519
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author Buffet, Alexandre
Calsina, Bruna
Flores, Shahida
Giraud, Sophie
Lenglet, Marion
Romanet, Pauline
Deflorenne, Elisa
Aller, Javier
Bourdeau, Isabelle
Bressac-de Paillerets, Brigitte
Calatayud, María
Dehais, Caroline
De Mones Del Pujol, Erwan
Elenkova, Atanaska
Herman, Philippe
Kamenický, Peter
Lejeune, Sophie
Sadoul, Jean Louis
Barlier, Anne
Richard, Stephane
Favier, Judith
Burnichon, Nelly
Gardie, Betty
Dahia, Patricia L
Robledo, Mercedes
Gimenez-Roqueplo, Anne-Paule
author_facet Buffet, Alexandre
Calsina, Bruna
Flores, Shahida
Giraud, Sophie
Lenglet, Marion
Romanet, Pauline
Deflorenne, Elisa
Aller, Javier
Bourdeau, Isabelle
Bressac-de Paillerets, Brigitte
Calatayud, María
Dehais, Caroline
De Mones Del Pujol, Erwan
Elenkova, Atanaska
Herman, Philippe
Kamenický, Peter
Lejeune, Sophie
Sadoul, Jean Louis
Barlier, Anne
Richard, Stephane
Favier, Judith
Burnichon, Nelly
Gardie, Betty
Dahia, Patricia L
Robledo, Mercedes
Gimenez-Roqueplo, Anne-Paule
author_sort Buffet, Alexandre
collection PubMed
description 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.
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spelling pubmed-73872102020-10-29 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 Buffet, Alexandre Calsina, Bruna Flores, Shahida Giraud, Sophie Lenglet, Marion Romanet, Pauline Deflorenne, Elisa Aller, Javier Bourdeau, Isabelle Bressac-de Paillerets, Brigitte Calatayud, María Dehais, Caroline De Mones Del Pujol, Erwan Elenkova, Atanaska Herman, Philippe Kamenický, Peter Lejeune, Sophie Sadoul, Jean Louis Barlier, Anne Richard, Stephane Favier, Judith Burnichon, Nelly Gardie, Betty Dahia, Patricia L Robledo, Mercedes Gimenez-Roqueplo, Anne-Paule J Med Genet Cancer Genetics 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. BMJ Publishing Group 2020-11 2020-01-29 /pmc/articles/PMC7387210/ /pubmed/31996412 http://dx.doi.org/10.1136/jmedgenet-2019-106519 Text en © Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ. http://creativecommons.org/licenses/by-nc/4.0/ http://creativecommons.org/licenses/by-nc/4.0/This is an open access article distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited, appropriate credit is given, any changes made indicated, and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/.
spellingShingle Cancer Genetics
Buffet, Alexandre
Calsina, Bruna
Flores, Shahida
Giraud, Sophie
Lenglet, Marion
Romanet, Pauline
Deflorenne, Elisa
Aller, Javier
Bourdeau, Isabelle
Bressac-de Paillerets, Brigitte
Calatayud, María
Dehais, Caroline
De Mones Del Pujol, Erwan
Elenkova, Atanaska
Herman, Philippe
Kamenický, Peter
Lejeune, Sophie
Sadoul, Jean Louis
Barlier, Anne
Richard, Stephane
Favier, Judith
Burnichon, Nelly
Gardie, Betty
Dahia, Patricia L
Robledo, Mercedes
Gimenez-Roqueplo, Anne-Paule
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
title 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Cancer Genetics
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7387210/
https://www.ncbi.nlm.nih.gov/pubmed/31996412
http://dx.doi.org/10.1136/jmedgenet-2019-106519
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