Rare variants modulating phenotype in NF1 carriers
Abstract Neurofibromatosis type 1 (NF1) is a rare genetic disorder with highly variable phenotypes, ranging from psychosocial challenges and congenital malformations to benign tumors and even aggressive cancers. We hypothesize that this variability stems from additional rare variants in other genes,...
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Nature Portfolio
2025-07-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-025-09751-z |
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| author | Elena Pasquinelli Giulia Casamassima Giulia Brunelli Omaima Belakhdar Samantha Minetto Salvatore Grosso Roberto Canitano Stefania Marsili Ignazio Martellucci Salvadora Tindara Miano Roberto Petrioli Margherita Baldassarri Romina D’Aurizio Chiara Fallerini Alessandra Renieri |
| author_facet | Elena Pasquinelli Giulia Casamassima Giulia Brunelli Omaima Belakhdar Samantha Minetto Salvatore Grosso Roberto Canitano Stefania Marsili Ignazio Martellucci Salvadora Tindara Miano Roberto Petrioli Margherita Baldassarri Romina D’Aurizio Chiara Fallerini Alessandra Renieri |
| author_sort | Elena Pasquinelli |
| collection | DOAJ |
| description | Abstract Neurofibromatosis type 1 (NF1) is a rare genetic disorder with highly variable phenotypes, ranging from psychosocial challenges and congenital malformations to benign tumors and even aggressive cancers. We hypothesize that this variability stems from additional rare variants in other genes, in addition to NF1 variants. The analysis of 32 NF1 patients revealed that those with solid cancers carried a higher average of cancer driver variants especially in DNA repair genes compared to those without (p < 0.05). An extended validation study using 217 NF1 carriers (71 cancer and 146 controls) from UK biobank confirmed significant enrichment of pathogenic (P), likely pathogenic (LP) and uncertain significant (VUS) variants in DNA repair genes, in NF1 patients with tumors (FDR ≤ 0.05). Furthermore, P/LP variants in other genes are shown in those patients with NF1 ancillary traits such as cognitive impairments, macrocephaly, and connective defects. This study provides novel evidence suggesting that additional genetic variants in other genes may contribute to the phenotypic variability observed in NF1, indicating that rare secondary mutational events could influence specific manifestations, adding complexity to its variable expressivity. |
| format | Article |
| id | doaj-art-56f88d4dc170436e8ef060a8ccea6d2f |
| institution | Kabale University |
| issn | 2045-2322 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj-art-56f88d4dc170436e8ef060a8ccea6d2f2025-08-20T03:42:25ZengNature PortfolioScientific Reports2045-23222025-07-0115111110.1038/s41598-025-09751-zRare variants modulating phenotype in NF1 carriersElena Pasquinelli0Giulia Casamassima1Giulia Brunelli2Omaima Belakhdar3Samantha Minetto4Salvatore Grosso5Roberto Canitano6Stefania Marsili7Ignazio Martellucci8Salvadora Tindara Miano9Roberto Petrioli10Margherita Baldassarri11Romina D’Aurizio12Chiara Fallerini13Alessandra Renieri14Medical Genetics, University of SienaMedical Genetics, University of SienaMedical Genetics, University of SienaMedical Genetics, University of SienaMedical Genetics, University of SienaClinical Pediatrics, Department of Molecular Medicine and Development, University of SienaDivision of Child and Adolescent Neuropsychiatry, University of SienaOncology, Azienda Ospedaliera Universitaria SeneseOncology, Azienda Ospedaliera Universitaria SeneseOncology, Azienda Ospedaliera Universitaria SeneseOncology, Azienda Ospedaliera Universitaria SeneseMedical Genetics, University of SienaInstitute of Informatics and Telematics, CNRMedical Genetics, University of SienaMedical Genetics, University of SienaAbstract Neurofibromatosis type 1 (NF1) is a rare genetic disorder with highly variable phenotypes, ranging from psychosocial challenges and congenital malformations to benign tumors and even aggressive cancers. We hypothesize that this variability stems from additional rare variants in other genes, in addition to NF1 variants. The analysis of 32 NF1 patients revealed that those with solid cancers carried a higher average of cancer driver variants especially in DNA repair genes compared to those without (p < 0.05). An extended validation study using 217 NF1 carriers (71 cancer and 146 controls) from UK biobank confirmed significant enrichment of pathogenic (P), likely pathogenic (LP) and uncertain significant (VUS) variants in DNA repair genes, in NF1 patients with tumors (FDR ≤ 0.05). Furthermore, P/LP variants in other genes are shown in those patients with NF1 ancillary traits such as cognitive impairments, macrocephaly, and connective defects. This study provides novel evidence suggesting that additional genetic variants in other genes may contribute to the phenotypic variability observed in NF1, indicating that rare secondary mutational events could influence specific manifestations, adding complexity to its variable expressivity.https://doi.org/10.1038/s41598-025-09751-z |
| spellingShingle | Elena Pasquinelli Giulia Casamassima Giulia Brunelli Omaima Belakhdar Samantha Minetto Salvatore Grosso Roberto Canitano Stefania Marsili Ignazio Martellucci Salvadora Tindara Miano Roberto Petrioli Margherita Baldassarri Romina D’Aurizio Chiara Fallerini Alessandra Renieri Rare variants modulating phenotype in NF1 carriers Scientific Reports |
| title | Rare variants modulating phenotype in NF1 carriers |
| title_full | Rare variants modulating phenotype in NF1 carriers |
| title_fullStr | Rare variants modulating phenotype in NF1 carriers |
| title_full_unstemmed | Rare variants modulating phenotype in NF1 carriers |
| title_short | Rare variants modulating phenotype in NF1 carriers |
| title_sort | rare variants modulating phenotype in nf1 carriers |
| url | https://doi.org/10.1038/s41598-025-09751-z |
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