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Family history of TGCT and its presence in twins support the involvement of inherited genetic factors. Germline exome sequencing was performed on monozygotic twins with TGCT and their parents. The twins presented compound heterozygous variants in PDE11A (rs776984134 and rs17400325) inherited from each parent. The rs776984134 variant disrupts the canonical splice acceptor site, leading to aberrant splicing and a frameshift predicted to affect protein structure. The rs17400325 missense variant, located in the catalytic domain, reduces hydrogen bonding capacity and may impair protein stability. Both variants map to a genomic region overlapping the antisense lncRNA PDE11A-AS1. In silico transcript-level analysis predicted multiple energetically favorable RNA\u2013RNA interactions between PDE11A and PDE11A-AS1 transcripts, with rs17400325 located within predicted hybridization regions of several isoforms. These results suggest a potential impact on PDE11A\u2013PDE11A-AS1 pairing and post-transcriptional regulation. Additional variants in MSH6 and CTU2 were also identified and may act as potential modifiers of disease susceptibility, consistent with a multigenic contribution to TGCT risk. These findings support a contributory role for the PDE11A locus in TGCT predisposition and underscore the biological relevance of overlapping sense\u2013antisense genomic regions in hereditary cancer studies.<\/jats:p>","DOI":"10.3390\/ijms27125261","type":"journal-article","created":{"date-parts":[[2026,6,11]],"date-time":"2026-06-11T02:59:31Z","timestamp":1781146771000},"page":"5261","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Family-Based Study Reveals PDE11A\/PDE11A-AS1 Variants in Testicular Germ Cell Tumor Predisposition"],"prefix":"10.3390","volume":"27","author":[{"given":"Luiza","family":"C\u00f4rtes","sequence":"first","affiliation":[{"name":"Botucatu Medical School Hospital (HCFMB), S\u00e3o Paulo State University\u2014UNESP, Botucatu 18618-687, SP, Brazil"},{"name":"Graduation Program in Genetics, Biosciences Institute, S\u00e3o Paulo State University\u2014UNESP, Botucatu 18618-689, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ana Beatriz","family":"Rodrigues","sequence":"additional","affiliation":[{"name":"Botucatu Medical School Hospital (HCFMB), S\u00e3o Paulo State University\u2014UNESP, Botucatu 18618-687, SP, Brazil"},{"name":"Graduation Program in Genetics, Biosciences Institute, S\u00e3o Paulo State University\u2014UNESP, Botucatu 18618-689, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0002-0868-856X","authenticated-orcid":false,"given":"Sara Martoreli","family":"Silveira","sequence":"additional","affiliation":[{"name":"Teaching Department, Universidade Nove de Julho (UNINOVE), S\u00e3o Paulo 01504-001, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4787-7147","authenticated-orcid":false,"given":"Julieta M.","family":"Ram\u00edrez-Mej\u00eda","sequence":"additional","affiliation":[{"name":"Laboratorio de Biolog\u00eda y Control de Enfermedades Infecciosas (BCEI), Sede de Investigaci\u00f3n Universitaria (SIU), Facultad de Ciencias Exactas y Naturales, Instituto de Biolog\u00eda, Universidad de Antioquia, Medell\u00edn 050010, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3353-3500","authenticated-orcid":false,"given":"Carine Spenassatto","family":"Dreyer","sequence":"additional","affiliation":[{"name":"Botucatu Medical School Hospital (HCFMB), S\u00e3o Paulo State University\u2014UNESP, Botucatu 18618-687, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4742-7047","authenticated-orcid":false,"given":"Mads M.","family":"Aagaard","sequence":"additional","affiliation":[{"name":"Clinical Genetics Department, University Hospital of Southern Denmark, 7100 Vejle, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8493-1587","authenticated-orcid":false,"given":"Geysson Javier","family":"Fernandez","sequence":"additional","affiliation":[{"name":"Laboratorio de Biolog\u00eda y Control de Enfermedades Infecciosas (BCEI), Sede de Investigaci\u00f3n Universitaria (SIU), Facultad de Ciencias Exactas y Naturales, Instituto de Biolog\u00eda, Universidad de Antioquia, Medell\u00edn 050010, Colombia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ademar","family":"Lopes","sequence":"additional","affiliation":[{"name":"Department of Pelvic Surgery, A.C. 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Trindade","family":"Filho","sequence":"additional","affiliation":[{"name":"Botucatu Medical School Hospital (HCFMB), S\u00e3o Paulo State University\u2014UNESP, Botucatu 18618-687, SP, Brazil"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4637-5687","authenticated-orcid":false,"given":"Silvia Regina","family":"Rogatto","sequence":"additional","affiliation":[{"name":"Botucatu Medical School Hospital (HCFMB), S\u00e3o Paulo State University\u2014UNESP, Botucatu 18618-687, SP, Brazil"},{"name":"Clinical Genetics Department, University Hospital of Southern Denmark, 7100 Vejle, Denmark"},{"name":"Institute of Regional Health Research, University of Southern Denmark, 5230 Odense, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,6,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"20151","DOI":"10.1038\/s41598-024-70552-x","article-title":"miR-21, miR-29a, and miR-106b: Serum and Tissue Biomarkers with Diagnostic Potential in Metastatic Testicular Cancer","volume":"14","author":"Ujfaludi","year":"2024","journal-title":"Sci. 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