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.
- von Hippel-Lindau
- cryptic exon
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BC, SF, SG and ML contributed equally.
Contributors APGR conceived and supervised the study. ABu, APGR, MR, PLD and BG designed the study and analysed the results. JF and NB participated to the data analysis. ABu., BC, SF, SG, ML and ED designed and performed the experiments. PR, JA, IB, BBdP, MC, CD EdM, AE, PH, PK, SL, JLS, ABa, SR, BG, PLD, MR and APGR collected subjects and clinical parameters. ABu and APGR wrote the manuscript. ABu prepared the figures and the tables. All the authors discussed the results and commented the manuscript.
Funding ABu received a financial support from ITMO Cancer AVIESAN (Alliance Nationale pour les Sciences de la Vie et de la Santé, National Alliance for Life Sciences & Health) within the framework of the Cancer Plan and from la Fondation pour la Recherche Médicale (FDT20170436955). SF is currently supported by an NIH-NIGMS individual predoctoral fellowship grant (F31-GM131634-01) and, previously, by an NIH NRSA Institutional Predoctoral Training Grant T32CA148724 and NRSA F31-GM131634-01. PLD receives funding support from NIH-GM114102, Alex’s Lemonade Stand Cancer Foundation (Innovation Award) and the NCATS- UL1 TR002645. The Genomic Sequencing Facility at the GCCRI is supported by the P30-CA54174 (CTRC at UTHSCSA) and NIH Shared Instrument grant 1S10OD021805-01 (S10 grant). BC is supported by Rafael del Pino Foundation. MR receives funding support from Instituto de Salud Carlos III (ISCIII), through the 'Acción Estratégica en Salud' (AES) (projects PI17/01796), cofounded by the European Regional Development Fund (ERDF), and the Paradifference Foundation.
Disclaimer The content is solely the responsibility of the authors and does not necessarily represent the official views of the NIH.
Competing interests None declared.
Patient consent for publication Not required.
Provenance and peer review Not commissioned; externally peer reviewed.
Data availability statement All available data are in the article.
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